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Rasool D, Jahani-Asl A. Master regulators of neurogenesis: the dynamic roles of Ephrin receptors across diverse cellular niches. Transl Psychiatry 2024; 14:462. [PMID: 39505843 PMCID: PMC11541728 DOI: 10.1038/s41398-024-03168-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 09/20/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
The ephrin receptors (EphRs) are the largest family of receptor tyrosine kinases (RTKs) that are abundantly expressed in the developing brain and play important roles at different stages of neurogenesis ranging from neural stem cell (NSC) fate specification to neural migration, morphogenesis, and circuit assembly. Defects in EphR signalling have been associated with several pathologies including neurodevelopmental disorders (NDDs), intellectual disability (ID), and neurodegenerative diseases (NDs). Here, we review our current understanding of the complex and dynamic role of EphRs in the brain and discuss how deregulation of these receptors contributes to disease, highlighting their potential as valuable druggable targets.
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Affiliation(s)
- Dilan Rasool
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
| | - Arezu Jahani-Asl
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada.
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada.
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Montréal, QC, H4A 3T2, Canada.
- Regenerative Medicine Program, and Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
- Ottawa Institutes of System Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
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2
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McRae HM, Leong MPY, Bergamasco MI, Garnham AL, Hu Y, Corbett MA, Whitehead L, El-Saafin F, Sheikh BN, Wilcox S, Hannan AJ, Gécz J, Smyth GK, Thomas T, Voss AK. Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome. PLoS Genet 2024; 20:e1011428. [PMID: 39405291 PMCID: PMC11478892 DOI: 10.1371/journal.pgen.1011428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/11/2024] [Indexed: 10/19/2024] Open
Abstract
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.
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Affiliation(s)
- Helen M. McRae
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Melody P. Y. Leong
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Maria I. Bergamasco
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Alexandra L. Garnham
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Yifang Hu
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Mark A. Corbett
- Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Lachlan Whitehead
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Farrah El-Saafin
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Bilal N. Sheikh
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Stephen Wilcox
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Anthony J. Hannan
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Jozef Gécz
- Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Gordon K. Smyth
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia
| | - Tim Thomas
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Anne K. Voss
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
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3
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Rasool D, Burban A, Sharanek A, Madrigal A, Hu J, Yan K, Qu D, Voss AK, Slack RS, Thomas T, Bonni A, Picketts DJ, Soleimani VD, Najafabadi HS, Jahani-Asl A. PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS. EMBO Rep 2024; 25:1256-1281. [PMID: 38429579 PMCID: PMC10933485 DOI: 10.1038/s44319-024-00082-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 03/03/2024] Open
Abstract
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
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Affiliation(s)
- Dilan Rasool
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montréal, QC, H4A 3J1, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
| | - Audrey Burban
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Montréal, QC, H4A 3T2, Canada
| | - Ahmad Sharanek
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Montréal, QC, H4A 3T2, Canada
| | - Ariel Madrigal
- Department of Human Genetics, McGill University, 3640 Rue University, Montréal, QC, H3A OC7, Canada
- McGill Genome Centre, Dahdaleh Institute of Genomic Medicine, 740 Dr Penfield Avenue, Montréal, QC, H3A 0G1, Canada
| | - Jinghua Hu
- Regenerative Medicine Program and Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
| | - Keqin Yan
- Regenerative Medicine Program and Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
| | - Dianbo Qu
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Anne K Voss
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3052, Australia
| | - Ruth S Slack
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Tim Thomas
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, VIC, 3052, Australia
| | - Azad Bonni
- Roche Pharma Research and Early Development (pRED), Roche Innovation Center, F. Hoffmann-La Roche Ltd., Basel, Switzerland
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - David J Picketts
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Regenerative Medicine Program and Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
- Departments of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H8M5, Canada
| | - Vahab D Soleimani
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montréal, QC, H4A 3J1, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Department of Human Genetics, McGill University, 3640 Rue University, Montréal, QC, H3A OC7, Canada
- Departments of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H8M5, Canada
| | - Hamed S Najafabadi
- Department of Human Genetics, McGill University, 3640 Rue University, Montréal, QC, H3A OC7, Canada.
- McGill Genome Centre, Dahdaleh Institute of Genomic Medicine, 740 Dr Penfield Avenue, Montréal, QC, H3A 0G1, Canada.
| | - Arezu Jahani-Asl
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- University of Ottawa, Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montréal, QC, H4A 3J1, Canada.
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada.
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Montréal, QC, H4A 3T2, Canada.
- Regenerative Medicine Program and Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
- Ottawa Institutes of System Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
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Jain V, Foo SH, Chooi S, Moss C, Goodwin R, Berland S, Clarke AJ, Davies SJ, Corrin S, Murch O, Doyle S, Graham GE, Greenhalgh L, Holder SE, Johnson D, Kumar A, Ladda RL, Sell S, Begtrup A, Lynch SA, McCann E, Østern R, Pottinger C, Splitt M, Fry AE. Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families. Eur J Hum Genet 2023; 31:1421-1429. [PMID: 37704779 PMCID: PMC10689765 DOI: 10.1038/s41431-023-01447-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 05/15/2023] [Accepted: 08/03/2023] [Indexed: 09/15/2023] Open
Abstract
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.
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Affiliation(s)
- Vani Jain
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK.
| | - Seow Hoong Foo
- Department of Dermatology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, UK
- Department of Dermatology, Gleneagles Hospital Medini, Nusajaya, 79250, Johor, Malaysia
| | - Stephen Chooi
- School of Medicine, Cardiff University, Heath Park Campus, Cardiff, CF14 4YS, UK
| | - Celia Moss
- Department of Dermatology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B4 6NH, UK
- University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Richard Goodwin
- Department of Dermatology, Royal Gwent Hospital, Newport, NP20 2UB, UK
| | - Siren Berland
- Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway
| | - Angus J Clarke
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
- Division of Cancer and Genetics, Cardiff University, Cardiff, CF14 4XN, UK
| | - Sally J Davies
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
| | - Sian Corrin
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
| | - Oliver Murch
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
| | - Samantha Doyle
- Department of Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, D12 N512, Ireland
- Department of Clinical Genetics, The National Maternity Hospital, Holles Street, Dublin, D02 YH21, Ireland
| | - Gail E Graham
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, K1H 8L1, Canada
| | - Lynn Greenhalgh
- Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, L8 7SS, UK
| | - Susan E Holder
- North West Thames Regional Genetic Service, Kennedy Galton Centre, Northwick Park Hospital, Harrow, HA1 3UJ, UK
| | - Diana Johnson
- Department of Clinical Genetics, Northern General Hospital, Sheffield, S5 7AU, UK
| | - Ajith Kumar
- North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, WC1N 3JH, UK
| | - Roger L Ladda
- Department of Pediatrics, Division of Human Genetics, Penn State Health Children's Hospital, Hershey, Pennsylvania, 17033, USA
| | - Susan Sell
- Department of Pediatrics, Division of Human Genetics, Penn State Health Children's Hospital, Hershey, Pennsylvania, 17033, USA
| | | | - Sally A Lynch
- Department of Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, D12 N512, Ireland
| | - Emma McCann
- Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, L8 7SS, UK
| | - Rune Østern
- Department of Medical Genetics, St. Olavs Hospital, Trondheim University Hospital, 7030, Trondheim, Norway
| | - Caroline Pottinger
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
| | - Miranda Splitt
- Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK
| | - Andrew E Fry
- All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK.
- Division of Cancer and Genetics, Cardiff University, Cardiff, CF14 4XN, UK.
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Hameed M, Siddiqui F, Sheikh FH, Khan MK, Admani B, Gangishetti PK. Borjeson-Forssman-Lehmann Syndrome: Clinical Features and Diagnostic Challenges. BRAIN & NEUROREHABILITATION 2023; 16:e32. [PMID: 38047102 PMCID: PMC10689860 DOI: 10.12786/bn.2023.16.e32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 09/23/2023] [Accepted: 10/02/2023] [Indexed: 12/05/2023] Open
Abstract
Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive disorder resulting from mutations in the PHF6 gene. The syndrome is characterized by short stature, obesity, hypogonadism, hypotonia, intellectual disability, distinctive facial features, fleshy ears, and finger and toe abnormalities. However, the diagnostic challenge in identifying BFLS remains a topic of interest. In this case report, we present the clinical characteristics of a proband with BFLS, highlighting the additional features of hypotonia, intellectual disability, and distinctive facial features. While no definitive treatment exists for BFLS, patients benefit from specialized education and ongoing supervision from early childhood through adulthood. Symptomatic treatment, including close follow-up, may be necessary for complications such as seizures and hearing problems. Mastectomy or testosterone replacement therapy may be considered on a case-by-case basis. Genetic counseling for X-linkage should be offered to affected families.
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Affiliation(s)
- Marya Hameed
- National Institute of Child health, Karachi, Pakistan
| | | | | | | | - Bushra Admani
- Dow University of Health Sciences, Karachi, Pakistan
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6
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Eisa YA, Guo Y, Yang FC. The Role of PHF6 in Hematopoiesis and Hematologic Malignancies. Stem Cell Rev Rep 2023; 19:67-75. [PMID: 36008597 DOI: 10.1007/s12015-022-10447-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/29/2023]
Abstract
Epigenetic regulation of gene expression represents an important mechanism in the maintenance of stem cell function. Alterations in epigenetic regulation contribute to the pathogenesis of hematological malignancies. Plant homeodomain finger protein 6 (PHF6) is a member of the plant homeodomain (PHD)-like zinc finger family of proteins that is involved in transcriptional regulation through the modification of the chromatin state. Germline mutation of PHF6 is the causative genetic alteration of the X-linked mental retardation Borjeson-Forssman-Lehmann syndrome (BFLS). Somatic mutations in PHF6 are identified in human leukemia, such as adult T-cell acute lymphoblastic leukemia (T-ALL, ~ 38%), pediatric T-ALL (~ 16%), acute myeloid leukemia (AML, ~ 3%), chronic myeloid leukemia (CML, ~ 2.5%), mixed phenotype acute leukemia (MPAL, ~ 20%), and high-grade B-cell lymphoma (HGBCL, ~ 3%). More recent studies imply an oncogenic effect of PHF6 in B-cell acute lymphoblastic leukemia (B-ALL) and solid tumors. These data demonstrate that PHF6 could act as a double-edged sword, either a tumor suppressor or an oncogene, in a lineage-dependent manner. However, the underlying mechanisms of PHF6 in normal hematopoiesis and leukemogenesis remain largely unknown. In this review, we summarize current knowledge of PHF6, emphasizing the role of PHF6 in hematological malignancies. Epigenetic regulation of PHF6 in B-ALL. PHF6 maintains a chromatin structure that is permissive to B-cell identity genes, but not T-cell-specific genes (left). Loss of PHF6 leads to aberrant expression of B-cell- and T-cell-specific genes resulting from lineage promiscuity and binding of T-cell transcription factors (right).
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Affiliation(s)
- Yusra A Eisa
- Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Ying Guo
- Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Feng-Chun Yang
- Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA. .,Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA.
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7
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Gerber CB, Fliedner A, Bartsch O, Berland S, Dewenter M, Haug M, Hayes I, Marin‐Reina P, Mark PR, Martinez‐Castellano F, Maystadt I, Karadurmus D, Steindl K, Wiesener A, Zweier M, Sticht H, Zweier C. Further characterization of
Borjeson‐Forssman‐Lehmann
syndrome in females due to
de novo
variants in
PHF6
. Clin Genet 2022; 102:182-190. [PMID: 35662002 PMCID: PMC9543785 DOI: 10.1111/cge.14173] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 11/28/2022]
Abstract
While inherited hemizygous variants in PHF6 cause X‐linked recessive Borjeson‐Forssman‐Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X‐inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two‐exon deletion, five truncating, one splice‐site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender‐specific phenotypes in addition to or in combination with effects of X‐inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype–phenotype correlations between females and males.
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Affiliation(s)
- Céline B. Gerber
- Department of Human Genetics, Inselspital, Bern University Hospital University of Bern Bern Switzerland
| | - Anna Fliedner
- Institute of Human Genetics, Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | - Oliver Bartsch
- Institute of Human Genetics University Medical Center of the Johannes Gutenberg‐University Mainz Mainz Germany
| | - Siren Berland
- Department of Medical Genetics Haukeland University Hospital Bergen Norway
| | - Malin Dewenter
- Institute of Human Genetics University Medical Center of the Johannes Gutenberg‐University Mainz Mainz Germany
| | - Marte Haug
- Department of Medical Genetics St. Olav's University Hospital Trondheim Norway
| | - Ian Hayes
- Genetic Health Service New Zealand, Auckland Hospital Auckland New Zealand
| | - Purificacion Marin‐Reina
- Genetics Unit / Department of Pediatrics and Medical Genetics University and Polytechnic Hospital La Fe Valencia Spain
| | - Paul R. Mark
- Spectrum Health Division of Medical and Molecular Genetics Grand Rapids Michigan USA
| | - Francisco Martinez‐Castellano
- Genetics Unit / Department of Pediatrics and Medical Genetics University and Polytechnic Hospital La Fe Valencia Spain
| | - Isabelle Maystadt
- Center for Human Genetics Institute of Pathology and Genetics Gosselies Belgium
| | - Deniz Karadurmus
- Center for Human Genetics Institute of Pathology and Genetics Gosselies Belgium
| | - Katharina Steindl
- Institute of Medical Genetics, University of Zurich, Schlieren‐Zurich Switzerland
| | - Antje Wiesener
- Institute of Human Genetics, Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | - Markus Zweier
- Institute of Medical Genetics, University of Zurich, Schlieren‐Zurich Switzerland
| | - Heinrich Sticht
- Institute of Biochemistry, Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
| | - Christiane Zweier
- Department of Human Genetics, Inselspital, Bern University Hospital University of Bern Bern Switzerland
- Institute of Human Genetics, Friedrich‐Alexander‐Universität Erlangen‐Nürnberg Erlangen Germany
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8
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Rosenberg AGW, Pater MRA, Pellikaan K, Davidse K, Kattentidt-Mouravieva AA, Kersseboom R, Bos-Roubos AG, van Eeghen A, Veen JMC, van der Meulen JJ, van Aalst-van Wieringen N, Hoekstra FME, van der Lely AJ, de Graaff LCG. What Every Internist-Endocrinologist Should Know about Rare Genetic Syndromes in Order to Prevent Needless Diagnostics, Missed Diagnoses and Medical Complications: Five Years of 'Internal Medicine for Rare Genetic Syndromes'. J Clin Med 2021; 10:jcm10225457. [PMID: 34830739 PMCID: PMC8622899 DOI: 10.3390/jcm10225457] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Pediatric multidisciplinary (MD) care has improved life expectancy, however, transfer to internal medicine is hindered by the lack of adequate MD care for adults. We have launched an MD outpatient clinic providing syndrome-specific care for adults with CRGS, which, to our knowledge, is the first one worldwide in the field of internal medicine. Between 2015 and 2020, we have treated 720 adults with over 60 syndromes. Eighty-nine percent of the syndromes were associated with endocrine problems. We describe case series of missed diagnoses and patients who had undergone extensive diagnostic testing for symptoms that could actually be explained by their syndrome. Based on our experiences and review of the literature, we provide an algorithm for the clinical approach of health problems in CRGS adults. We conclude that missed diagnoses and needless invasive tests seem common in CRGS adults. Due to the increased life expectancy, an increasing number of patients with CRGS will transfer to adult endocrinology. Internist-endocrinologists (in training) should be aware of their special needs and medical pitfalls of CRGS will help prevent the burden of unnecessary diagnostics and under- and overtreatment.
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Affiliation(s)
- Anna G. W. Rosenberg
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
- Dutch Center of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands
| | - Minke R. A. Pater
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
| | - Karlijn Pellikaan
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
- Dutch Center of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands
| | - Kirsten Davidse
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
- Dutch Center of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands
| | | | - Rogier Kersseboom
- Stichting Zuidwester, 3241 LB Middelharnis, The Netherlands; (A.A.K.-M.); (R.K.)
| | - Anja G. Bos-Roubos
- Center of Excellence for Neuropsychiatry, Vincent van Gogh, 5803 DN Venray, The Netherlands;
| | - Agnies van Eeghen
- ‘s Heeren Loo, Care Group, 3818 LA Amersfoort, The Netherlands;
- Department of Pediatrics, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Academic Center for Growth Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - José M. C. Veen
- ‘s Heeren Loo, Care Providing Agency, 6733 SC Wekerom, The Netherlands; (J.M.C.V.); (J.J.v.d.M.)
| | - Jiske J. van der Meulen
- ‘s Heeren Loo, Care Providing Agency, 6733 SC Wekerom, The Netherlands; (J.M.C.V.); (J.J.v.d.M.)
| | - Nina van Aalst-van Wieringen
- Department of Physical Therapy, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
| | - Franciska M. E. Hoekstra
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
- Department of Internal Medicine, Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands
| | - Aart J. van der Lely
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
| | - Laura C. G. de Graaff
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (A.G.W.R.); (M.R.A.P.); (K.P.); (K.D.); (F.M.E.H.); (A.J.v.d.L.)
- Dutch Center of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands
- Academic Center for Growth Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- ENCORE—Dutch Center of Reference for Neurodevelopmental Disorders, 3015 GD Rotterdam, The Netherlands
- Dutch Center of Reference for Turner Syndrome, 3015 GD Rotterdam, The Netherlands
- Dutch Center of Reference for Disorders of Sex Development, 3015 GD Rotterdam, The Netherlands
- Correspondence:
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9
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Yau T, Bansal R, Hardin K, Senders C, Nandalike K. Nasal trumpet as a long-term remedy for obstructive sleep apnea syndrome in a child. SAGE Open Med Case Rep 2021; 9:2050313X211055303. [PMID: 34721876 PMCID: PMC8554540 DOI: 10.1177/2050313x211055303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/06/2021] [Indexed: 11/17/2022] Open
Abstract
We present a case of successful long-term use of nasal trumpet for severe obstructive sleep apnea syndrome in a child with cerebral palsy and complex medical issues. Obstructive sleep apnea syndrome is frequently seen in pediatric patients with cerebral palsy due to their abnormal airway tone and pulmonary vulnerability. Identifying children with cerebral palsy who are at risk for obstructive sleep apnea syndrome is important because its treatment can improve quality of life and seizure control. Although first-line treatment for obstructive sleep apnea syndrome is adenotonsillectomy, children with cerebral palsy are more likely to have residual obstructive sleep apnea syndrome postoperatively. Other options such as positive airway pressure therapy and other upper airway surgeries may pose significant challenges and tolerance issues, as in our patient. As demonstrated in our report, the low rate of complications and ease of use make nasal trumpets a potential long-term treatment option for children with obstructive sleep apnea syndrome who fail or cannot comply with the traditional treatment options.
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Affiliation(s)
- Tammy Yau
- Department of Pediatrics, University of California Davis Health, Sacramento, CA, USA
| | - Ruchi Bansal
- Department of Pulmonary and Critical Care Medicine, Delano Regional Medical Center, Delano, CA, USA
| | - Kimberly Hardin
- Department of Pulmonary and Critical Care Medicine, University of California Davis Health, Sacramento, CA, USA
| | - Craig Senders
- Department of Otolaryngology, University of California Davis Health, Sacramento, CA, USA
| | - Kiran Nandalike
- Division of Pulmonary Medicine, Department of Pediatrics, University of California Davis Health, Sacramento, CA, USA
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10
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Ahmed R, Sarwar S, Hu J, Cardin V, Qiu LR, Zapata G, Vandeleur L, Yan K, Lerch JP, Corbett MA, Gecz J, Picketts DJ. Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome. Hum Mol Genet 2021; 30:575-594. [PMID: 33772537 PMCID: PMC8120135 DOI: 10.1093/hmg/ddab081] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/24/2021] [Accepted: 03/16/2021] [Indexed: 12/26/2022] Open
Abstract
The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.
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Affiliation(s)
- Raies Ahmed
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
- Departments of Biochemistry, Microbiology, & Immunology, Ottawa, Ontario K1H 8M5, Canada
| | - Shihab Sarwar
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
| | - Jinghua Hu
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
| | - Valérie Cardin
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
- Cellular & Molecular Medicine, Ottawa, Ontario K1H 8M5, Canada
| | - Lily R Qiu
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada
- Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
| | - Gerardo Zapata
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
- Departments of Biochemistry, Microbiology, & Immunology, Ottawa, Ontario K1H 8M5, Canada
| | - Lucianne Vandeleur
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Keqin Yan
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
| | - Jason P Lerch
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada
- Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Mark A Corbett
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Jozef Gecz
- Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
- South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - David J Picketts
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada
- Departments of Biochemistry, Microbiology, & Immunology, Ottawa, Ontario K1H 8M5, Canada
- Cellular & Molecular Medicine, Ottawa, Ontario K1H 8M5, Canada
- Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
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11
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Toral-Lopez J, Huerta LMG, Messina-Baas O, Cuevas-Covarrubias SA. Submicroscopic 11p13 deletion including the elongator acetyltransferase complex subunit 4 gene in a girl with language failure, intellectual disability and congenital malformations: A case report. World J Clin Cases 2020; 8:5296-5303. [PMID: 33269262 PMCID: PMC7674752 DOI: 10.12998/wjcc.v8.i21.5296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/08/2020] [Accepted: 09/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We described the main features of an infant diagnosed with facial dysmorphic, language failure, intellectual disability and congenital malformations to strengthen our understanding of the disease. Currently, treatment is only rehabilitation and surgery for cleft lip and palate. CASE SUMMARY The proband was a 2-years-8-months-old girl. Familial history was negative for congenital malformations or intellectual disability. The patient had microcephaly, upward-slanting palpebral fissures, depressed nasal bridge, bulbous nose and bilateral cleft lip and palate. Brain magnetic resonance imaging showed cortical atrophy and band heterotopia. Her motor and intellectual development is delayed. A submicroscopic deletion in 11p13 involving the elongator acetyltransferase complex subunit 4 gene (ELP4) and a loss of heterozygosity in Xq25-q26.3 were detected. CONCLUSION There is no treatment for the ELP4 deletion caused by a submicroscopic 11p3 deletion. We describe a second case of deletion of the ELP4 gene without aniridia, which confirms the association between ELP4 gene with several defects and absence of this ocular defect. Additional clinical data in the deletion of the ELP4 gene as cleft palate, facial dysmorphism, and changes at level brain could be associated to this gene or be part of the effect of the recessives genes involved in the loss of heterozygosity region of Xq25-26.3.
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Affiliation(s)
- Jaime Toral-Lopez
- Departamento de Genética Medica, Centro Medico Ecatepec, ISSEMYM, Ecatepec 55000, México
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud/Hospital Infantil de México, Universidad Nacional Autónoma de México, México 06720, México
| | | | - Olga Messina-Baas
- Departamento de Oftalmología, Hospital General de México, Cuauhtémoc 06720, México
| | - Sergio A Cuevas-Covarrubias
- Genetica, Hospital General de México, Cuauhtémoc 06726, Mexico
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México, México 06720, Mexico
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12
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Loss of PHF6 leads to aberrant development of human neuron-like cells. Sci Rep 2020; 10:19030. [PMID: 33149206 PMCID: PMC7642390 DOI: 10.1038/s41598-020-75999-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/22/2020] [Indexed: 11/09/2022] Open
Abstract
Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson-Forssman-Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females. To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of PHF6, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR/Cas9 to induce knockout of PHF6 in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of PHF6 loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.
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13
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McRae HM, Eccles S, Whitehead L, Alexander WS, Gécz J, Thomas T, Voss AK. Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome. Development 2020; 147:dev.187021. [PMID: 32994169 DOI: 10.1242/dev.187021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 09/09/2020] [Indexed: 12/28/2022]
Abstract
Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6 - /Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.
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Affiliation(s)
- Helen M McRae
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.,Department of Medical Biology, The University of Melbourne, Victoria 3052, Australia
| | - Samantha Eccles
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia
| | - Lachlan Whitehead
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.,Department of Medical Biology, The University of Melbourne, Victoria 3052, Australia
| | - Warren S Alexander
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.,Department of Medical Biology, The University of Melbourne, Victoria 3052, Australia
| | - Jozef Gécz
- Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Tim Thomas
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia .,Department of Medical Biology, The University of Melbourne, Victoria 3052, Australia
| | - Anne K Voss
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia .,Department of Medical Biology, The University of Melbourne, Victoria 3052, Australia
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14
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Bellad A, Bandari AK, Pandey A, Girimaji SC, Muthusamy B. A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome. J Mol Neurosci 2020; 70:1403-1409. [PMID: 32399860 DOI: 10.1007/s12031-020-01560-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/22/2020] [Indexed: 12/27/2022]
Abstract
Börjeson-Forssman-Lehman Syndrome (BFLS) is a rare X-linked recessive syndrome characterized by intellectual disability, developmental delay, obesity, epilepsy, swelling of the subcutaneous tissues of the face, large but not deformed ears, hypogonadism, and gynecomastia. Pathogenic mutations in PHD finger protein 6 (PHF6) have been reported to cause BFLS. In this study, we describe two male siblings with mild intellectual disability, global developmental delay, short stature, microcephaly, and nyctalopia. Whole exome sequencing of the affected siblings and the parents identified a missense variant (c.413C > G) in the PHF6 gene, which leads to alteration of a serine residue at position 138 to cysteine. This mutation is located in a highly conserved region. Sanger sequencing confirmed the segregation of this mutation in the family in an X-linked recessive fashion. Multiple mass spectrometry-based proteomic studies have reported phosphorylation at serine 138 that describes the possible role of serine 138 in signaling. This novel variant in PHF6 gene helped in establishing a diagnosis of BFLS.
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Affiliation(s)
- Anikha Bellad
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Aravind K Bandari
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Satish Chandra Girimaji
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Child and Adolescent Psychiatry, NIMHANS, Hosur Road, Bangalore, 560029, India.
| | - Babylakshmi Muthusamy
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
- Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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15
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Gianni F, Belver L, Ferrando A. The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med 2020; 10:a035246. [PMID: 31570389 PMCID: PMC7050584 DOI: 10.1101/cshperspect.a035246] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T-cell progenitors. The recognition of clinical, genetic, transcriptional, and biological heterogeneity in this disease has already translated into new prognostic biomarkers, improved leukemia animal models, and emerging targeted therapies. This work reviews our current understanding of the molecular mechanisms of T-ALL.
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Affiliation(s)
- Francesca Gianni
- Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA
| | - Laura Belver
- Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA
| | - Adolfo Ferrando
- Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA
- Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA
- Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA
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16
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Zhang X, Fan Y, Liu X, Zhu MA, Sun Y, Yan H, He Y, Ye X, Gu X, Yu Y. A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome. J Clin Res Pediatr Endocrinol 2019; 11:419-425. [PMID: 30630810 PMCID: PMC6878345 DOI: 10.4274/jcrpe.galenos.2019.2018.0220] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by PHF6 mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of PHF6 gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.
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Affiliation(s)
- Xia Zhang
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China,These authors contributed equally to this work
| | - Yanjie Fan
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China,These authors contributed equally to this work.,* Address for Correspondence: Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China Phone: +862125076466, +862125076453 E-mail:,
| | - Xiaomin Liu
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Ming-Ang Zhu
- Shanghai Jiaotong University School of Medicine, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, The Laboratory of Pediatric Infectious Diseases, Shanghai, China
| | - Yu Sun
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Hui Yan
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Yunjuan He
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Xiantao Ye
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Xuefan Gu
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China
| | - Yongguo Yu
- Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China,* Address for Correspondence: Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, Shanghai Institute for Pediatric Research, Department of Pediatric Endocrinology and Genetics, Shanghai, China Phone: +862125076466, +862125076453 E-mail:,
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17
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Marques P, Korbonits M. Pseudoacromegaly. Front Neuroendocrinol 2019; 52:113-143. [PMID: 30448536 DOI: 10.1016/j.yfrne.2018.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/30/2018] [Accepted: 11/14/2018] [Indexed: 01/19/2023]
Abstract
Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly.
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Affiliation(s)
- Pedro Marques
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
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Kasper BS, Dörfler A, Di Donato N, Kasper EM, Wieczorek D, Hoyer J, Zweier C. Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome. Epilepsy Behav 2017; 69:104-109. [PMID: 28237832 DOI: 10.1016/j.yebeh.2017.01.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 01/18/2017] [Accepted: 01/18/2017] [Indexed: 02/07/2023]
Abstract
Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare disorder caused by mutations in the PHF6 gene. It manifests as syndromic X-linked recessive intellectual disability (ID) in males and as sporadic ID due to de novo mutations in females. Clinical features include variable ID and a range of somatic manifestations constituting a distinct phenotype in both males and females, respectively, including seizures in a few. Central nervous system (CNS) imaging data are largely unavailable for BFLS. Here we report on CNS MRI findings from two female individuals with BFLS due to a de novo duplication in PHF6 who presented with typical BFLS and epilepsy. Brain findings encompass an intriguing combination of structural abnormalities including a simplified gyral pattern and aspects resembling subcortical band heterotopia as signs of malformation of cortical development (MCD). This finding is of note, since PHF6 has been suggested to play pivotal roles in CNS development including neuronal migration.
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Affiliation(s)
- Burkhard S Kasper
- Epilepsy Center, Dept. Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany.
| | - Arnd Dörfler
- Dept. Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen, Germany
| | - Nataliya Di Donato
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307, Dresden, Germany
| | - Ekkehard M Kasper
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Dagmar Wieczorek
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany; Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Juliane Hoyer
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christiane Zweier
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
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Jahani-Asl A, Cheng C, Zhang C, Bonni A. Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function. Neurobiol Dis 2016; 96:227-235. [PMID: 27633282 DOI: 10.1016/j.nbd.2016.09.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 08/07/2016] [Accepted: 09/07/2016] [Indexed: 02/07/2023] Open
Abstract
Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability. Recent studies have uncovered mechanisms by which mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). PHF6 plays a critical role in the migration of neurons in the mouse cerebral cortex in vivo, and patient-specific mutations disrupt the ability of PHF6 to promote neuronal migration. Interestingly, PHF6 physically associates with the PAF1 transcriptional elongation complex and thereby drives neuronal migration in the cerebral cortex. PHF6 also interacts with the NuRD chromatin remodeling complex and with the nucleolar transcriptional regulator UBF, though the biological role of these interactions remains to be characterized. In other studies, PHF6 mRNA has been identified as the target of the microRNA miR-128 in the cerebral cortex, providing new insights into regulation of PHF6 function in neuronal migration. Importantly, deregulation of PHF6 function in neuronal migration triggers the formation of white matter heterotopias that harbor neuronal hyperexcitability, which may be relevant to the pathogenesis of intellectual disability and seizures in BFLS. Collectively, these studies are beginning to provide key insights into the molecular pathogenesis of BFLS.
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Affiliation(s)
- Arezu Jahani-Asl
- Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA; Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
| | - Cheng Cheng
- Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA
| | - Chi Zhang
- Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA
| | - Azad Bonni
- Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA.
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Todd MAM, Huh MS, Picketts DJ. The sub-nucleolar localization of PHF6 defines its role in rDNA transcription and early processing events. Eur J Hum Genet 2016; 24:1453-9. [PMID: 27165002 PMCID: PMC5027685 DOI: 10.1038/ejhg.2016.40] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/30/2016] [Accepted: 04/12/2016] [Indexed: 12/20/2022] Open
Abstract
Ribosomal RNA synthesis occurs in the nucleolus and is a tightly regulated process that is targeted in some developmental diseases and hyperactivated in multiple cancers. Subcellular localization and immunoprecipitation coupled mass spectrometry demonstrated that a proportion of plant homeodomain (PHD) finger protein 6 (PHF6) protein is localized within the nucleolus and interacts with proteins involved in ribosomal processing. PHF6 sequence variants cause Börjeson–Forssman–Lehmann syndrome (BFLS, MIM#301900) and are also associated with a female-specific phenotype overlapping with Coffin–Siris syndrome (MIM#135900), T-cell acute lymphoblastic leukemia (MIM#613065), and acute myeloid leukemia (MIM#601626); however, very little is known about its cellular function, including its nucleolar role. HEK 293T cells were treated with RNase A, DNase I, actinomycin D, or 5,6-dichloro-β-D-ribofuranosylbenzimadole, followed by immunocytochemistry to determine PHF6 sub-nucleolar localization. We observed RNA-dependent localization of PHF6 to the sub-nucleolar fibrillar center (FC) and dense fibrillar component (DFC), at whose interface rRNA transcription occurs. Subsequent ChIP-qPCR analysis revealed strong enrichment of PHF6 across the entire rDNA-coding sequence but not along the intergenic spacer (IGS) region. When rRNA levels were quantified in a PHF6 gain-of-function model, we observed an overall decrease in rRNA transcription, accompanied by a modest increase in repressive promoter-associated RNA (pRNA) and a significant increase in the expression levels of the non-coding IGS36RNA and IGS39RNA transcripts. Collectively, our results demonstrate a role for PHF6 in carefully mediating the overall levels of ribosome biogenesis within a cell.
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Affiliation(s)
- Matthew A M Todd
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Michael S Huh
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - David J Picketts
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Bao Y, Liu Z, Zhang J, Wu J, Shi Y. 1H, 13C and 15N resonance assignments and secondary structure of the human PHF6-ePHD1 domain. BIOMOLECULAR NMR ASSIGNMENTS 2016; 10:1-4. [PMID: 26286319 DOI: 10.1007/s12104-015-9627-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 08/11/2015] [Indexed: 06/04/2023]
Abstract
The plant homeodomain (PHD) finger 6 (PHF6) is a multidomain protein that comprises four nuclear localization signals and two extended PHD zinc finger domains (ePHD), suggesting that the PHD domains of PHF6 may have different functions compared with other PHD domains. And the PHF6 was first identified as the gene mutated associated with Börjeson-Forssman-Lehmann syndrome, an X-linked mental retardation disorder. The mutant PHF6 is also associated with T cell acute lymphoblastic leukemia and acute myeloid leukemia. But the molecular mechanism between these diseases and PHF6 are still unclear. In addition, the first conserved ePHD (ePHD1) of PHF6 is involved in its nucleolus localization, directly interacts with upstream binding factor (UBF) and suppresses rRNA transcription. Here we show the backbone resonance and side chain assignments of the PHF6-ePHD1 domain from human by heteronuclear multidimensional NMR spectroscopy and its secondary structure as predicted by the TALOS+. These assignments of PHF6-ePHD1 domain throw a light on the further structure determination, dynamics and interaction with UBF.
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Affiliation(s)
- Yun Bao
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Zhonghua Liu
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Jiahai Zhang
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Jihui Wu
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China.
| | - Yunyu Shi
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China.
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Abstract
BACKGROUND To examine the contribution of generational epigenetic dysregulation to the inception of obesity and its adiposopathic consequences. METHODS Sources for this review included searches of PubMed, Google Scholar, and international government/major association websites using terms including adiposity, adiposopathy, epigenetics, genetics, and obesity. RESULTS Excessive energy storage in adipose tissue often results in fat cell and fat organ dysfunction, which may cause metabolic and fat mass disorders. The adverse clinical manifestations of obesity are not solely due to the amount of body fat (adiposity), but are also dependent on anatomical and functional perturbations (adiposopathy or 'sick fat'). This review describes extragenetic factors and genetic conditions that promote obesity. It also serves as an introduction to epigenetic dysregulation (i.e., abnormalities in gene expression that occur without alteration in the genetic code itself), which may contribute to obesity and adiposopathic metabolic health outcomes in offspring. Within the epigenetic paradigm, obesity is a transgenerational disease, with weight lost or gained by either parent potentially impacting generational risk for obesity and its complications. CONCLUSIONS Epigenetics may be an important contributor to the emergence of obesity and its complications as global epidemics. Although transgenerational epigenetic influences present challenges, they may also present interventional opportunities, via justifying weight management for individuals before, during, and after pregnancy and for future generations.
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Affiliation(s)
- Harold Bays
- a a Louisville Metabolic and Atherosclerosis Research Center (L-MARC) , Louisville , KY , USA
| | - Wendy Scinta
- b b Medical Weight Loss of NY , Fayetteville , NY , USA
- c c State University of New York , Upstate Department of Family Medicine , Syracuse , NY , USA
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Ernst A, Le VQ, Højland AT, Pedersen IS, Sørensen TH, Bjerregaard LL, Lyngbye TJB, Gammelager NM, Krarup H, Petersen MB. The PHF6 Mutation c.1A>G; pM1V Causes Börjeson-Forsman-Lehmann Syndrome in a Family with Four Affected Young Boys. Mol Syndromol 2015; 6:181-6. [PMID: 26648834 DOI: 10.1159/000441047] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2015] [Indexed: 11/19/2022] Open
Abstract
The family presented with 4 boys, 2 sets of brothers, with unexplained intellectual disability. Numerous analyses had been conducted over more than a decade, without reaching a final clinical or molecular diagnosis. According to the pedigree, an X-linked inheritance pattern was strongly suspected. Whole-exome sequencing (WES) with targeted analysis of the coding regions of the X chromosome was carried out in the 4 boys, their mothers, and their shared grandmother. A filtering process searching for nonsynonymous variants and variants in the exon-intron boundaries revealed one variant, c.1A>G; pM1V, in the first codon of the PHF6 gene. The variant was hemizygous in the 4 boys and heterozygous in the 2 mothers and the grandmother. Mutations in the PHF6 gene are known to cause Börjeson-Forsman-Lehmann syndrome (BFLS). The boys were reexamined after the finding of the mutation, and the phenotype fitted perfectly with BFLS. The mutation found in the PHF6 gene is causative for the intellectual disability in this family. We also conclude that WES of the X chromosome is a powerful tool in families where an X-linked inheritance pattern is suspected.
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Affiliation(s)
- Anja Ernst
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Vang Q Le
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Allan T Højland
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
| | - Inge S Pedersen
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Tine H Sørensen
- Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark
| | | | - Troels J B Lyngbye
- Center for Deafblindness and Hearing Impairment, Aalborg, Denmark ; Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| | - Ninna M Gammelager
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
| | - Henrik Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Michael B Petersen
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein. Genes (Basel) 2015; 6:325-52. [PMID: 26103525 PMCID: PMC4488667 DOI: 10.3390/genes6020325] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 06/12/2015] [Accepted: 06/16/2015] [Indexed: 12/13/2022] Open
Abstract
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.
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Van der Meulen J, Van Roy N, Van Vlierberghe P, Speleman F. The epigenetic landscape of T-cell acute lymphoblastic leukemia. Int J Biochem Cell Biol 2014; 53:547-57. [PMID: 24786297 DOI: 10.1016/j.biocel.2014.04.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 04/08/2014] [Accepted: 04/10/2014] [Indexed: 12/29/2022]
Abstract
The genetic landscape of T-ALL has been very actively explored during the past decades. This leads to an overwhelming body of exciting novel findings providing insight into (1) the genetic heterogeneity of the disease with marked genetic subsets, (2) the mechanisms by which aberrant T-cell development drive leukemogenesis and (3) emerging opportunities for novel therapeutic interventions. Of further interest, recent genome wide sequencing studies identified proteins that actively participate in the regulation of the T-cell epigenome as novel oncogenes and tumor suppressor genes in T-ALL. The identification of these perturbed molecular epigenetic events in the pathogenesis of T-ALL will contribute to the further exploration of novel therapies in this cancer type. As some epigenetic therapies have recently been approved for a number of hematological neoplasms, one could speculate that targeted therapies against epigenetic regulators might offer good prospects for T-ALL treatment in the near future. In this review, we summarize the epigenetic discoveries made in T-ALL hitherto and discuss possible new venues for epigenetic therapeutic intervention in this aggressive subtype of human leukemia. This article is part of a Directed Issue entitled: Rare Cancers.
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Affiliation(s)
| | - Nadine Van Roy
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | | | - Frank Speleman
- Center for Medical Genetics, Ghent University, Ghent, Belgium.
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Liu Z, Li F, Ruan K, Zhang J, Mei Y, Wu J, Shi Y. Structural and functional insights into the human Börjeson-Forssman-Lehmann syndrome-associated protein PHF6. J Biol Chem 2014; 289:10069-83. [PMID: 24554700 DOI: 10.1074/jbc.m113.535351] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The plant homeodomain finger 6 (PHF6) was originally identified as the gene mutated in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome. Mutations in the PHF6 gene have also been associated with T-cell acute lymphoblastic leukemia and acute myeloid leukemia. Approximately half of the disease-associated mutations are distributed in the second conserved extended plant homeodomain (ePHD2) of PHF6, indicating the functional importance of the ePHD2 domain. Here, we report the high resolution crystal structure of the ePHD2 domain of PHF6, which contains an N-terminal pre-PHD (C2HC zinc finger), a long linker, and an atypical PHD finger. PHF6-ePHD2 appears to fold as a novel integrated structural module. Structural analysis of PHF6-ePHD2 reveals pathological implication of PHF6 gene mutations in Börjeson-Forssman-Lehmann syndrome, T-cell acute lymphoblastic leukemia, and acute myeloid leukemia. The binding experiments show that PHF6-ePHD2 can bind dsDNA but not histones. We also demonstrate PHF6 protein directly interacts with the nucleosome remodeling and deacetylation complex component RBBP4. Via this interaction, PHF6 exerts its transcriptional repression activity. Taken together, these data support the hypothesis that PHF6 may function as a transcriptional repressor using its ePHD domains binding to the promoter region of its repressed gene, and this process was regulated by the nucleosome remodeling and deacetylation complex that was recruited to the genomic target site by NoLS region of PHF6.
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Affiliation(s)
- Zhonghua Liu
- From the Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
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X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity. Orphanet J Rare Dis 2013; 8:146. [PMID: 24053514 PMCID: PMC4015352 DOI: 10.1186/1750-1172-8-146] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 09/15/2013] [Indexed: 12/14/2022] Open
Abstract
X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature. We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions.
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Phadke SR, Ranganath P, Boggula VR, Gupta D, Phadke RV, Sloman M, Turnpenny PD. Brothers with hypospadias, vertebral segmentation defects, and intellectual disability: New syndrome? Am J Med Genet A 2012; 158A:3065-70. [DOI: 10.1002/ajmg.a.35607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 07/16/2012] [Indexed: 11/09/2022]
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Li X, Yao H, Chen Z, Wang Q, Zhao Y, Chen S. Somatic mutations of PHF6 in patients with chronic myeloid leukemia in blast crisis. Leuk Lymphoma 2012; 54:671-2. [PMID: 22928734 DOI: 10.3109/10428194.2012.725203] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Todd MAM, Picketts DJ. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex. J Proteome Res 2012; 11:4326-37. [PMID: 22720776 DOI: 10.1021/pr3004369] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Mutations in PHF6 are the cause of Börjeson-Forssman-Lehman syndrome (BFLS), an X-linked intellectual disability (XLID) disorder, and both T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). The PHF6 gene encodes a protein with two plant homeodomain (PHD)-like zinc finger domains. As many PHD-like domains function to target chromatin remodelers to post-translationally modified histones, this suggests a role for PHF6 in chromatin regulation. However, PHD domains are usually found in association with a catalytic domain, a feature that is lacking in PHF6. This distinct domain structure and the minimal information on its cellular function prompted us to perform a proteomic screen to identify PHF6 binding partners. We expressed recombinant Flag-tagged PHF6 in HEK 293T cells for coimmunoprecipitation, and analyzed the purified products by mass spectrometry. We identified proteins involved in ribosome biogenesis, RNA splicing, and chromatin regulation, consistent with PHF6 localization to both the nucleoplasm and nucleolus. Notably, PHF6 copurified with multiple constituents of the nucleosome remodeling and deacetylation (NuRD) complex, including CHD4, HDAC1, and RBBP4. We demonstrate that this PHF6-NuRD complex is not present in the nucleolus but is restricted to the nucleoplasm. The association with NuRD represents the first known interaction for PHF6 and implicates it in chromatin regulation.
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Affiliation(s)
- Matthew A M Todd
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8L6
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Yoo NJ, Kim YR, Lee SH. Somatic mutation of PHF6 gene in T-cell acute lymphoblatic leukemia, acute myelogenous leukemia and hepatocellular carcinoma. Acta Oncol 2012; 51:107-11. [PMID: 21736506 DOI: 10.3109/0284186x.2011.592148] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Somatic mutations in plant homeodomain finger protein 6 (PHF6) gene have recently been reported in T-cell acute lymphoblastic leukemia (T-ALL), strongly suggesting its role in the pathogenesis of human cancers. MATERIALS AND METHODS To see whether the PHF6 mutation occurs in other malignancies, we analyzed entire coding sequences of PHF6 in 231 hematologic malignancies [105 acute myelogenous leukemias (AML), 66 pre-B-ALL, 23 T-ALL, one undifferentiated acute leukemia and 36 multiple myelomas] by single-strand conformation polymorphism assay. Also, we analyzed the mutation in 236 solid cancers, including 41 lung, 39 hepatocellular (HCC), 36 breast, 40 colorectal, 40 gastric and 40 prostate carcinomas. RESULTS In the hematologic malignancies, there were 11 PHF6 mutations that were detected not only in T-ALL (34.7%) (five adult and three childhood T-ALL), but also in two AML (1.9%) (one acute monocytic leukemia and one AML minimally differentiated). In addition, there was a PHF6 mutation in the HCC (2.6%). The PHF6 mutations were detected in both male and female patients, and consisted of six frameshift, three nonsense and two intron mutations. CONCLUSION Our data suggest that PHF6 mutation might play a role in tumorigenesis not only of T-ALL, but also of AML and HCC.
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Affiliation(s)
- Nam Jin Yoo
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Berland S, Alme K, Brendehaug A, Houge G, Hovland R. PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females. Mol Syndromol 2011; 1:294-300. [PMID: 22190899 DOI: 10.1159/000330111] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2011] [Indexed: 12/20/2022] Open
Abstract
In a 16-year-old girl with intellectual disability, irregular teeth, slight body asymmetry, and striated skin pigmentation, highly skewed X-inactivation increased the likelihood of an X-linked cause of her condition. Among these, prominent supraorbital ridges and hearing loss suggested a filaminopathy, but no filamin A mutation was found. The correct diagnosis, Borjeson-Forssman-Lehmann syndrome (BFLS, MIM#301900), was first made when a copy number array identified a de novo 15-kb deletion of the terminal 3 exons of the PHF6 gene. In retrospect, her phenotype resembled that of males with BFLS. Such deletions of PHF6 have not been reported previously. This might be because PHF6 mutations are rarely looked for in females since classical BFLS so far has been thought to be a male-specific syndrome, and large PHF6 deletions might be incompatible with male fetal survival. If this is the case, sporadic BFLS could be more frequent in females than in males.
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Affiliation(s)
- S Berland
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen
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Chao MM, Todd MA, Kontny U, Neas K, Sullivan MJ, Hunter AG, Picketts DJ, Kratz CP. T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6. Pediatr Blood Cancer 2010; 55:722-4. [PMID: 20806366 PMCID: PMC2933084 DOI: 10.1002/pbc.22574] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL.
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Affiliation(s)
- Mwe Mwe Chao
- Division of Pediatric Hematology-Oncology, Children’s National Medical Center, Washington, DC, USA
| | - Matthew A. Todd
- Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Udo Kontny
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
| | - Katherine Neas
- Central and Southern Regional Genetics Service, Capital and Coast District Health Board, Wellington, New Zealand
| | - Michael J. Sullivan
- Department of Paediatrics, Children's Cancer Research Group, Children's Haematology Oncology Centre, Christchurch School of Medicine, University of Otago, Christchurch, New Zealand
| | - Alasdair G. Hunter
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - David J. Picketts
- Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Christian P. Kratz
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
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Ding F, Li HH, Li J, Myers RM, Francke U. Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice. PLoS One 2010; 5:e9402. [PMID: 20195375 PMCID: PMC2827556 DOI: 10.1371/journal.pone.0009402] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Accepted: 01/14/2010] [Indexed: 02/07/2023] Open
Abstract
Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to maternal deprivation in neonatal wild-type and Snord116del mice, a mouse model for PWS in which a cluster of imprinted C/D box snoRNAs is deleted. The neonatal starvation response in both strains was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation showed no expression change in the hypothalamus of 5 day-old pups after 6 hours of maternal deprivation. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndp, Brms1l, Mett10d, and Snx1 were decreased after neonatal deprivation. In addition, we compared hypothalamic gene expression profiles at postnatal days 5 and 13 and observed significant developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at all time points and conditions, arguing against a role of Snord116 in feeding regulation in the neonatal period.
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Affiliation(s)
- Feng Ding
- Department of Genetics, Stanford University, Stanford, California, United States of America
| | - Hong Hua Li
- Department of Genetics, Stanford University, Stanford, California, United States of America
| | - Jun Li
- Department of Genetics, Stanford University, Stanford, California, United States of America
| | - Richard M. Myers
- Department of Genetics, Stanford University, Stanford, California, United States of America
| | - Uta Francke
- Department of Genetics, Stanford University, Stanford, California, United States of America
- * E-mail:
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Kousta E, Hadjiathanasiou CG, Tolis G, Papathanasiou A. Pleiotropic genetic syndromes with developmental abnormalities associated with obesity. J Pediatr Endocrinol Metab 2009; 22:581-92. [PMID: 19774839 DOI: 10.1515/jpem.2009.22.7.581] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Childhood obesity is a common and complex problem that may persist in adulthood. It may present as a component of genetic syndromes associated with dysmorphic features, developmental abnormalities, mental retardation and/or learning disabilities and often neuroendocrine dysfunction. Although the chromosomal abnormalities of these rare syndromes are already known, the specific genetic and pathophysiological mechanisms leading to the distinct phenotypes and obesity still remain unclarified. New exciting genetic pathways contributing to syndrome phenotype and leading to obesity have recently been identified. Prader-Willi syndrome is caused by loss of expression of the C/D box HBII-84 cluster of snoRNAs. Dysfunction of the primary cilium, thought to have important signalling functions, may contribute to disease phenotype and obesity in Bardet-Biedl, Alstrom and Carpenter syndromes. In this mini-review current knowledge of clinical and genetic characteristics is summarized as well as the pathogenesis of these syndromes with special emphasis on the pathogenesis of obesity.
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Affiliation(s)
- Eleni Kousta
- Department of Endocrinology, P & A Kyriakou Children's Hospital, Athens, Greece.
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Mangelsdorf M, Chevrier E, Mustonen A, Picketts DJ. Börjeson-Forssman-Lehmann Syndrome due to a novel plant homeodomain zinc finger mutation in the PHF6 gene. J Child Neurol 2009; 24:610-4. [PMID: 19264739 DOI: 10.1177/0883073808327830] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The Börjeson-Forssman-Lehmann syndrome is an X-linked mental retardation disorder caused by mutations in the PHF6 gene. The PHF6 gene contains 2 plant homeodomain zinc fingers, suggesting a role for the protein in chromatin remodeling. In this study, the authors report on a Finnish family with a classical Börjeson-Forssman-Lehmann syndrome phenotype caused by a G to T nucleotide substitution at position 266 within exon 4 within the PHF6 gene (c.266G>T). The resulting glycine to valine (p.G89V) change corresponds to a highly conserved residue within the first plant homeodomain zinc finger domain. This is a novel change that adds to the number of plant homeodomain zinc finger mutations identified, such that 23% of all Börjeson-Forssman-Lehmann syndrome mutations lie within this motif. Moreover, it highlights the functional importance of plant homeodomain zinc finger motifs to human disease and more specifically to PHF6 function.
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Affiliation(s)
- Marie Mangelsdorf
- Regenerative Medicine Program, Ottawa Health Research Institute, Ontario, Canada
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Carter MT, Picketts DJ, Hunter AG, Graham GE. Further clinical delineation of the Börjeson-Forssman-Lehmann syndrome in patients with PHF6 mutations. Am J Med Genet A 2009; 149A:246-50. [PMID: 19161141 DOI: 10.1002/ajmg.a.32624] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Börjeson-Forssman-Lehmann syndrome is an X-linked condition caused by PHF6 mutations. The classical description of males with this disorder includes severe intellectual disability with epilepsy, microcephaly, short stature, obesity, hypogonadism, and gynecomastia. We present three males with PHF6 mutations whose features included deep-set eyes, large ears, coarse face, tapering fingers, and truncal obesity. Unlike the original description of the syndrome; however, the males described herein had varying degrees of intellectual disability and hypogonadism, were of normal to tall stature, had normal to large head sizes, and did not have seizures. This departure from the usual clinical description of Börjeson-Forssman-Lehmann syndrome is consistent with recent reports of males with mutations in PHF6. In addition, we describe the phenotype and X-inactivation pattern in two females heterozygous for PHF6 mutations, both of whom have mild features of the syndrome.
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Affiliation(s)
- Melissa T Carter
- Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
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de Winter CF, van Dijk F, Stolker JJ, Hennekam RCM. Behavioural phenotype in Börjeson-Forssman-Lehmann syndrome. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH : JIDR 2009; 53:319-328. [PMID: 19187102 DOI: 10.1111/j.1365-2788.2009.01156.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
BACKGROUND Börjeson-Forssman-Lehmann syndrome (BFLs) is an X-linked inherited disorder characterised by unusual facial features, abnormal fat distribution and intellectual disability. As many genetically determined disorders are characterised not only by physical features but also by specific behaviour, we studied whether a specific behavioural phenotype exists in BFLs. METHODS We studied in detail the behaviour of four molecularly proven BFLs patients, and reviewed available literature on BFLs specifically for behavioural characteristics. RESULTS Behaviour in persons with BFLs is in general friendly, but can be challenging with externalising and thrill-seeking features. Social skills are good. However, variation among patients is wide. Three patients from a single family showed expressed hypersexual behaviour. This was not present in other patients. CONCLUSION In BFLs a specific behavioural phenotype exists and in behaviour general is challenging besides a friendly habit. Within single families more problematic behaviour may occur. Further behavioural and molecular analysis of a larger group of patients is warranted to determine whether a genotype-behavioural phenotype correlation exists.
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Affiliation(s)
- C F de Winter
- Abrona, Institute for People with Intellectual Disabilities, Huis ter Heide, The Netherlands.
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Voss AK, Gamble R, Collin C, Shoubridge C, Corbett M, Gécz J, Thomas T. Protein and gene expression analysis of Phf6, the gene mutated in the Börjeson-Forssman-Lehmann Syndrome of intellectual disability and obesity. Gene Expr Patterns 2007; 7:858-71. [PMID: 17698420 DOI: 10.1016/j.modgep.2007.06.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2007] [Revised: 06/14/2007] [Accepted: 06/29/2007] [Indexed: 10/23/2022]
Abstract
The Plant homeodomain finger gene 6 (PHF6) was identified as the gene mutated in patients suffering from the Börjeson-Forssman-Lehmann Syndrome (BFLS), an X-linked mental retardation disorder. BFLS mental disability is evident from an early age, suggesting a developmental brain defect. The PHF6 protein contains four nuclear localisation signals and two imperfect plant homeodomain (PHD) fingers similar to the third, imperfect PHD fingers in members of the trithorax family of transcriptional regulators. The PHF6 gene is highly conserved in vertebrate species. Despite the devastating effects of mutation of the PHF6 gene, nothing is known about the cellular function of PHF6. In order to lay the base for functional studies, we identify here the cell types that express the murine Phf6 gene and protein during prenatal and postnatal development. The Phf6 gene and protein are expressed widely. However, expression levels vary from strong to barely detectable. Strongest Phf6 gene expression and nuclear localisation of Phf6 protein were observed in the developing central nervous system, the anterior pituitary gland, the primordia of facial structures and the limb buds. Expression levels of both mRNA and protein decline over the course of development. In the adult brain moderate Phf6 expression is maintained in projection neurons, such as mitral cells in the olfactory bulb, cerebrocortical pyramidal cells and cerebellar Purkinje cells. Phf6 gene expression and nuclear localisation of Phf6 protein correlate with clinical symptoms in BFLS patients, namely mental disability, pan-anterior pituitary hormonal deficiency and facial as well digit abnormalities.
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Affiliation(s)
- Anne K Voss
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic. 3050, Australia.
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