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Cocanougher BT, Liu SW, Francescatto L, Behura A, Anneling M, Jackson DG, Deak KL, Hornik CD, ElMallah MK, Pizoli CE, Smith EC, Tan KGQ, McDonald MT. The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt. HGG ADVANCES 2024; 5:100288. [PMID: 38566418 PMCID: PMC11070630 DOI: 10.1016/j.xhgg.2024.100288] [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: 11/28/2023] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/04/2024] Open
Abstract
Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.
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Affiliation(s)
- Benjamin T Cocanougher
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA.
| | - Samuel W Liu
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA
| | | | - Alexander Behura
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA
| | - Mariele Anneling
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA
| | - David G Jackson
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA
| | - Kristen L Deak
- Department of Pathology, Duke University, Durham, NC, USA
| | - Chi D Hornik
- Department of Pediatrics, Duke University, Durham, NC, USA
| | - Mai K ElMallah
- Department of Pediatrics, Duke University, Durham, NC, USA
| | - Carolyn E Pizoli
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Pediatric Neurology, Duke University, Durham, NC, USA
| | - Edward C Smith
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Pediatric Neurology, Duke University, Durham, NC, USA
| | - Khoon Ghee Queenie Tan
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA
| | - Marie T McDonald
- Department of Pediatrics, Duke University, Durham, NC, USA; Division of Medical Genetics, Duke University, Durham, NC, USA.
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Gelernter J, Levey DF, Galimberti M, Harrington K, Zhou H, Adhikari K, Gupta P, Gaziano JM, Eliott D, Stein MB. Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations. CELL GENOMICS 2024; 4:100582. [PMID: 38870908 PMCID: PMC11228954 DOI: 10.1016/j.xgen.2024.100582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/20/2024] [Accepted: 05/10/2024] [Indexed: 06/15/2024]
Abstract
Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.
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Affiliation(s)
- Joel Gelernter
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA; Departments of Genetics and Neuroscience, Yale School of Medicine, New Haven, CT, USA.
| | - Daniel F Levey
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA
| | - Marco Galimberti
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA
| | - Kelly Harrington
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA; Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Hang Zhou
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA
| | - Keyrun Adhikari
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA
| | - Priya Gupta
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Psychiatry, VA Connecticut Healthcare Center, West Haven, CT, USA
| | - J Michael Gaziano
- Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medicine, Divisions of Aging and Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Dean Eliott
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Murray B Stein
- University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA
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3
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Jühlen R, Grauer L, Martinelli V, Rencurel C, Fahrenkrog B. Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence. Sci Rep 2024; 14:1742. [PMID: 38242956 PMCID: PMC10799014 DOI: 10.1038/s41598-023-50615-1] [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: 06/15/2023] [Accepted: 12/22/2023] [Indexed: 01/21/2024] Open
Abstract
Fetal akinesia deformation sequence (FADS) represents the severest form of congenital myasthenic syndrome (CMS), a diverse group of inherited disorders characterised by impaired neuromuscular transmission. Most CMS originate from defects in the muscle nicotinic acetylcholine receptor, but the underlying molecular pathogenesis is only poorly understood. Here we show that RNAi-mediated silencing of FADS-related proteins rapsyn and NUP88 in foetal fibroblasts alters organisation of the actin cytoskeleton. We show that fibroblasts from two independent FADS individuals have enhanced and shorter actin stress fibre bundles, alongside with an increased number and size of focal adhesions, with an otherwise normal overall connectivity and integrity of the actin-myosin cytoskeleton network. By proximity ligation assays and bimolecular fluorescence complementation, we show that rapsyn and NUP88 localise nearby adhesion plaques and that they interact with the focal adhesion protein paxillin. Based on these findings we propose that a respective deficiency in rapsyn and NUP88 in FADS alters the regulation of actin dynamics at focal adhesions, and thereby may also plausibly dictate myofibril contraction in skeletal muscle of FADS individuals.
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Affiliation(s)
- Ramona Jühlen
- Laboratory Biology of the Cell Nucleus, Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium.
- Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany.
| | - Lukas Grauer
- Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany
| | - Valérie Martinelli
- Laboratory Biology of the Cell Nucleus, Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium
- Laboratory of Neurovascular Signaling, Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium
| | | | - Birthe Fahrenkrog
- Laboratory Biology of the Cell Nucleus, Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium.
- Biozentrum, University of Basel, 4056, Basel, Switzerland.
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4
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Jacob T, Annusver K, Czarnewski P, Dalessandri T, Kalk C, Levra Levron C, Campamà Sanz N, Kastriti ME, Mikkola ML, Rendl M, Lichtenberger BM, Donati G, Björklund ÅK, Kasper M. Molecular and spatial landmarks of early mouse skin development. Dev Cell 2023; 58:2140-2162.e5. [PMID: 37591247 PMCID: PMC11088744 DOI: 10.1016/j.devcel.2023.07.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 05/05/2023] [Accepted: 07/21/2023] [Indexed: 08/19/2023]
Abstract
A wealth of specialized cell populations within the skin facilitates its hair-producing, protective, sensory, and thermoregulatory functions. How the vast cell-type diversity and tissue architecture develops is largely unexplored. Here, with single-cell transcriptomics, spatial cell-type assignment, and cell-lineage tracing, we deconstruct early embryonic mouse skin during the key transitions from seemingly uniform developmental precursor states to a multilayered, multilineage epithelium, and complex dermal identity. We identify the spatiotemporal emergence of hair-follicle-inducing, muscle-supportive, and fascia-forming fibroblasts. We also demonstrate the formation of the panniculus carnosus muscle (PCM), sprouting blood vessels without pericyte coverage, and the earliest residence of mast and dendritic immune cells in skin. Finally, we identify an unexpected epithelial heterogeneity within the early single-layered epidermis and a signaling-rich periderm layer. Overall, this cellular and molecular blueprint of early skin development-which can be explored at https://kasperlab.org/tools-establishes histological landmarks and highlights unprecedented dynamic interactions among skin cells.
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Affiliation(s)
- Tina Jacob
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Karl Annusver
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Paulo Czarnewski
- Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, 17165 Stockholm, Sweden
| | - Tim Dalessandri
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Christina Kalk
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Chiara Levra Levron
- Department of Life Sciences and Systems Biology, Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy
| | - Nil Campamà Sanz
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Maria Eleni Kastriti
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Marja L Mikkola
- Cell and Tissue Dynamics Research Program, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland
| | - Michael Rendl
- Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Beate M Lichtenberger
- Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Giacomo Donati
- Department of Life Sciences and Systems Biology, Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy
| | - Åsa K Björklund
- Department of Life Science, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, 41296 Göteborg, Sweden
| | - Maria Kasper
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
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De Rose DU, Ronci S, Caoci S, Maddaloni C, Diodato D, Catteruccia M, Fattori F, Bosco L, Pro S, Savarese I, Bersani I, Randi F, Trozzi M, Meucci D, Calzolari F, Salvatori G, Solinas A, Dotta A, Campi F. Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature. J Pers Med 2023; 13:jpm13050798. [PMID: 37240968 DOI: 10.3390/jpm13050798] [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] [Received: 03/23/2023] [Revised: 04/21/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients' characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.
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Affiliation(s)
| | - Sara Ronci
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Stefano Caoci
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Chiara Maddaloni
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Daria Diodato
- Neuromuscular and Neurodegenerative Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Michela Catteruccia
- Neuromuscular and Neurodegenerative Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Fabiana Fattori
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy
| | - Luca Bosco
- Neuromuscular and Neurodegenerative Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
- Department of Science, University Roma Tre, 00146 Rome, Italy
| | - Stefano Pro
- Developmental Neurology Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Immacolata Savarese
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Iliana Bersani
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Franco Randi
- Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Marilena Trozzi
- Airway Surgery Unit, Pediatric Surgery Department, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Duino Meucci
- Airway Surgery Unit, Pediatric Surgery Department, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Flaminia Calzolari
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Guglielmo Salvatori
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Agostina Solinas
- Neonatal Intensive Care Unit, Sant'Anna Hospital of Ferrara, 44124 Ferrara, Italy
| | - Andrea Dotta
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
| | - Francesca Campi
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
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Prömer J, Barresi C, Herbst R. From phosphorylation to phenotype - Recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK. Cell Signal 2023; 104:110584. [PMID: 36608736 DOI: 10.1016/j.cellsig.2022.110584] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/16/2022] [Accepted: 12/31/2022] [Indexed: 01/04/2023]
Abstract
Muscle-specific kinase (MuSK) is the key regulator of neuromuscular junction development. MuSK acts via several distinct pathways and is responsible for pre- and postsynaptic differentiation. MuSK is unique among receptor tyrosine kinases as activation and signaling are particularly tightly regulated. Initiation of kinase activity requires Agrin, a heparan sulphate proteoglycan derived from motor neurons, the low-density lipoprotein receptor-related protein-4 (Lrp4) and the intracellular adaptor protein Dok-7. There is a great knowledge gap between MuSK activation and downstream signaling. Recent studies using omics techniques have addressed this knowledge gap, thereby greatly contributing to a better understanding of MuSK signaling. Impaired MuSK signaling causes severe muscle weakness as described in congenital myasthenic syndromes or myasthenia gravis but the underlying pathophysiology is often unclear. This review focuses on recent advances in deciphering MuSK activation and downstream signaling. We further highlight latest break-throughs in understanding and treatment of MuSK-related disorders and discuss the role of MuSK in non-muscle tissue.
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Affiliation(s)
- Jakob Prömer
- Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Cinzia Barresi
- Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ruth Herbst
- Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
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Ohno K, Ohkawara B, Shen XM, Selcen D, Engel AG. Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review. Int J Mol Sci 2023; 24:ijms24043730. [PMID: 36835142 PMCID: PMC9961056 DOI: 10.3390/ijms24043730] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/09/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.
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Affiliation(s)
- Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Correspondence: (K.O.); (A.G.E.)
| | - Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Xin-Ming Shen
- Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA
| | - Duygu Selcen
- Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA
| | - Andrew G. Engel
- Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence: (K.O.); (A.G.E.)
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Kapp ME, Lyle P, Nickols HH. Fetal akinesia deformation sequence with pontocerebellar hypoplasia, and migration and gyration defects. AUTOPSY AND CASE REPORTS 2021; 11:e2021323. [PMID: 34540727 PMCID: PMC8432359 DOI: 10.4322/acr.2021.323] [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: 05/20/2020] [Accepted: 07/09/2021] [Indexed: 11/23/2022] Open
Abstract
Fetal akinesia deformation sequence (FADS), or Pena-Shokeir phenotype is a constellation of deformational changes resulting from decreased or absent fetal movement, and include arthrogryposis, and craniofacial and central nervous system anomalies. We report an autopsy case of a 36-6/7week female neonate with a normal female karyotype and chromosome microarray demonstrating findings consistent with FADS. We provide a detailed examination of the severe and complex central nervous system abnormalities, including marked pontocerebellar hypoplasia and cortical and cerebellar migration and gyration defects. This case represents a rare detailed examination of the central nervous system of a patient with FADS.
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Affiliation(s)
- Meghan Elizabeth Kapp
- Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN, USA
| | - Pamela Lyle
- C.W. Bill Young VA Medical Center, Department of Pathology & Laboratory Medicine Services, Bay Pine, FL, USA
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Dahan-Oliel N, Dieterich K, Rauch F, Bardai G, Blondell TN, Gustafson AG, Hamdy R, Latypova X, Shazand K, Giampietro PF, van Bosse H. The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children. Genes (Basel) 2021; 12:genes12081220. [PMID: 34440395 PMCID: PMC8391526 DOI: 10.3390/genes12081220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/31/2021] [Accepted: 08/02/2021] [Indexed: 12/28/2022] Open
Abstract
Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age); the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS.
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Affiliation(s)
- Noémi Dahan-Oliel
- Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; (F.R.); (G.B.); (R.H.)
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
- Correspondence: (N.D.-O.); (H.v.B.)
| | - Klaus Dieterich
- Inserm, U1216, Grenoble Institut Neurosciences, Génétique médicale, Université Grenoble Alpes, CHU Grenoble Alpes, 38000 Grenoble, France; (K.D.); (X.L.)
| | - Frank Rauch
- Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; (F.R.); (G.B.); (R.H.)
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Ghalib Bardai
- Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; (F.R.); (G.B.); (R.H.)
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | | | | | - Reggie Hamdy
- Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; (F.R.); (G.B.); (R.H.)
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Xenia Latypova
- Inserm, U1216, Grenoble Institut Neurosciences, Génétique médicale, Université Grenoble Alpes, CHU Grenoble Alpes, 38000 Grenoble, France; (K.D.); (X.L.)
| | - Kamran Shazand
- Shriners Hospitals for Children Headquarters, Tampa, FL 33607, USA; (A.G.G.); (K.S.)
| | | | - Harold van Bosse
- Shriners Hospitals for Children, Philadelphia, PA 19140, USA;
- Correspondence: (N.D.-O.); (H.v.B.)
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10
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Zhang YJ, Yao Y, Zhang PD, Li ZH, Zhang P, Li FR, Wang ZH, Liu D, Lv YB, Kang L, Shi XM, Mao C. Association of regular aerobic exercises and neuromuscular junction variants with incidence of frailty: an analysis of the Chinese Longitudinal Health and Longevity Survey. J Cachexia Sarcopenia Muscle 2021; 12:350-357. [PMID: 33527771 PMCID: PMC8061381 DOI: 10.1002/jcsm.12658] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 11/15/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Candidate genes of neuromuscular junction (NMJ) pathway increased risk of frailty, but the extent and whether can be offset by exercises was unclear. The aim of this study was to investigate the association between aerobic exercises and incident frailty regardless of NMJ pathway-related genetic risk. METHODS A cohort study on participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2011. A total of 7006 participants (mean age of 80.6 ± 10.3 years) without frailty at baseline were interviewed to record aerobic exercise status, and 4053 individuals among them submitted saliva samples. NMJ pathway-related genes were genotyped and weighted genetic risk scores were constructed. RESULTS During a median follow-up of 3.1 years (19 634 person-years), there were 1345 cases (19.2%) of incident frailty. Persistent aerobic exercises were associated with a 26% lesser frailty risk [adjusted hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.64-0.85]. This association was stronger in a subgroup of 1552 longevous participants (age between 90 and 111 years, adjusted HR = 0.72, 95% CI = 0.60-0.87). High genetic risk was associated with a 35% increased risk of frailty (adjusted HR = 1.35, 95% CI = 1.16-1.58). Of the participants with high genetic risk and no persistent aerobic exercises, there was a 59% increased risk of frailty (adjusted HR = 1.59, 95% CI = 1.20-2.09). HRs for the risk of frailty increased from the low genetic risk with persistent aerobic exercise to high genetic risk without persistent aerobic exercise (P trend <0.001). CONCLUSIONS Both aerobic exercises and NMJ pathway-related genetic risk were significantly associated with frailty. Persistent aerobic exercises can partly offset NMJ pathway-related genetic risk to frailty in elderly people.
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Affiliation(s)
- Yu-Jie Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yao Yao
- Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China
| | - Pei-Dong Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zhi-Hao Li
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Pei Zhang
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Fu-Rong Li
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zheng-He Wang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Dan Liu
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yue-Bin Lv
- National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Lin Kang
- Department of Geriatrics, Peking Union Medical College Hospital, Beijing, China
| | - Xiao-Ming Shi
- National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Chen Mao
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
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11
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Jühlen R, Martinelli V, Vinci C, Breckpot J, Fahrenkrog B. Centrosome and ciliary abnormalities in fetal akinesia deformation sequence human fibroblasts. Sci Rep 2020; 10:19301. [PMID: 33168876 PMCID: PMC7652866 DOI: 10.1038/s41598-020-76192-1] [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: 06/02/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Ciliopathies are clinical disorders of the primary cilium with widely recognised phenotypic and genetic heterogeneity. Here, we found impaired ciliogenesis in fibroblasts derived from individuals with fetal akinesia deformation sequence (FADS), a broad spectrum of neuromuscular disorders arising from compromised foetal movement. We show that cells derived from FADS individuals have shorter and less primary cilia (PC), in association with alterations in post-translational modifications in α-tubulin. Similarly, siRNA-mediated depletion of two known FADS proteins, the scaffold protein rapsyn and the nucleoporin NUP88, resulted in defective PC formation. Consistent with a role in ciliogenesis, rapsyn and NUP88 localised to centrosomes and PC. Furthermore, proximity-ligation assays confirm the respective vicinity of rapsyn and NUP88 to γ-tubulin. Proximity-ligation assays moreover show that rapsyn and NUP88 are adjacent to each other and that the rapsyn-NUP88 interface is perturbed in the examined FADS cells. We suggest that the perturbed rapsyn-NUP88 interface leads to defects in PC formation and that defective ciliogenesis contributes to the pleiotropic defects seen in FADS.
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Affiliation(s)
- Ramona Jühlen
- Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium.,Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany
| | - Valérie Martinelli
- Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium
| | - Chiara Vinci
- Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium
| | - Jeroen Breckpot
- Center for Human Genetics, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium
| | - Birthe Fahrenkrog
- Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, 6041, Gosselies, Belgium. .,Biozentrum, University of Basel, 4056, Basel, Switzerland.
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12
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Torshin IY, Gromova OA, Stakhovskaya LV, Semenov VA, Shchukin IA. Chemotranscriptome analysis indicates the neurotrophic and neuromodulator effects of a citicoline molecule. ACTA ACUST UNITED AC 2020. [DOI: 10.14412/2074-2711-2020-4-91-99] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Objective: to investigate the effect of citicoline (CTC) on gene transcription.Material and methods. Chemotranscriptome analysis of the CTC molecule was carried out on an NPC.TAK model, provided that the cells were incubated with CTC for 24 hours.Results and discussion. CTC dose-dependently affected the transcription of 8,838 out of 12,716 annotated human genes, mainly by increasing the transcription of the genes involved: 1) in the neurotransmitter metabolism of serotonin (n=36), dopamine (n=32), GABA (n=14), and acetylcholine (n=27); 2) in showing the effects of neurotrophic factors (n=152), including nerve growth factor (n=11); 3) in maintaining the cardiovascular system (vasodilation and cardiac electrical activity; a total of 76 genes). CTC reduced the transcription of the genes, whose protein activity supported inflammation (n=86) and cell division (n=656). CTC elevated the expression of 60 genes involved in triglyceride processing and decreased the expression of 51 genes whose proteins were involved in cholesterol metabolism. CTC increased the transcription of the genes involved in the body’s response to various drugs, including antiepileptic drugs (n=20), dopaminergic agents (n=19), antipsychotics (n=38), anxiolytics (n=21), sedatives (n=22), antidepressants (n=35), anesthetics (n=23), and antidementia drugs (n=11).Conclusion. Chemotranscriptome analysis indicated the positive effect of CTC on neurotransmission, neuroprotection, lipid profile, and a higher neuronal susceptibility to other neuroactive drugs.
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Affiliation(s)
- I. Yu. Torshin
- Institute of Pharmacoinformatics, Federal Research Center «Informatics and Management», Russian Academy of Sciences; Center for Big Data Storage and Analysis, National Center for Digital Economy, M.V. Lomonosov Moscow State University
| | - O. A. Gromova
- Institute of Pharmacoinformatics, Federal Research Center «Informatics and Management», Russian Academy of Sciences; Center for Big Data Storage and Analysis, National Center for Digital Economy, M.V. Lomonosov Moscow State University
| | - L. V. Stakhovskaya
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
| | - V. A. Semenov
- Kemerovo State Medical University, Ministry of Health of Russia
| | - I. A. Shchukin
- N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
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13
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Ali A, Al-Tobasei R, Lourenco D, Leeds T, Kenney B, Salem M. Genome-wide scan for common variants associated with intramuscular fat and moisture content in rainbow trout. BMC Genomics 2020; 21:529. [PMID: 32736521 PMCID: PMC7393730 DOI: 10.1186/s12864-020-06932-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 07/20/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Genetic improvement of fillet quality attributes is a priority of the aquaculture industry. Muscle composition impacts quality attributes such as flavor, appearance, texture, and juiciness. Fat and moisture make up about ~ 80% of the tissue weight. The genetic architecture underlying the fat and moisture content of the muscle is still to be fully explored in fish. A 50 K gene transcribed SNP chip was used for genotyping 789 fish with available phenotypic data for fat and moisture content. Genotyped fish were obtained from two consecutive generations produced in the National Center for Cool and Cold Water Aquaculture (NCCCWA) growth-selective breeding program. Estimates of SNP effects from weighted single-step GBLUP (WssGBLUP) were used to perform genome-wide association (GWA) analysis to identify quantitative trait loci (QTL) associated with the studied traits. RESULTS Using genomic sliding windows of 50 adjacent SNPs, 137 and 178 SNPs were identified as associated with fat and moisture content, respectively. Chromosomes 19 and 29 harbored the highest number of SNPs explaining at least 2% of the genetic variation in fat and moisture content. A total of 61 common SNPs on chromosomes 19 and 29 affected the aforementioned traits; this association suggests common mechanisms underlying intramuscular fat and moisture content. Additionally, based on single-marker GWA analyses, 8 and 24 SNPs were identified in association with fat and moisture content, respectively. CONCLUSION SNP-harboring genes were primarily involved in lipid metabolism, cytoskeleton remodeling, and protein turnover. This work provides putative SNP markers that could be prioritized and used for genomic selection in breeding programs.
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Affiliation(s)
- Ali Ali
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA
| | - Rafet Al-Tobasei
- Computational Science Program, Middle Tennessee State University, Murfreesboro, TN, 37132, USA
| | - Daniela Lourenco
- Department of Animal and Dairy Science, University of Georgia, Athens, GA, 30602, USA
| | - Tim Leeds
- National Center for Cool and Cold Water Aquaculture, Agricultural Research Service, United States Department of Agriculture, Kearneysville, WV, USA
| | - Brett Kenney
- Division of Animal and Nutritional Sciences, West Virginia University, Morgantown, WV, 26506, USA
| | - Mohamed Salem
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA.
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14
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Multiple MuSK signaling pathways and the aging neuromuscular junction. Neurosci Lett 2020; 731:135014. [PMID: 32353380 DOI: 10.1016/j.neulet.2020.135014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 12/16/2022]
Abstract
The neuromuscular junction (NMJ) is the vehicle for fast, reliable and robust communication between motor neuron and muscle. The unparalleled accessibility of this synapse to morphological, electrophysiological and genetic analysis has yielded an in depth understanding of many molecular components mediating its formation, maturation and stability. However, key questions surrounding the signaling pathways mediating these events and how they play out across the lifetime of the synapse remain unanswered. Such information is critical since the NMJ is necessary for normal movement and is compromised in several settings including myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), muscular dystrophy, sarcopenia and aging. Muscle specific kinase (MuSK) is a central player in most if not all contexts of NMJ formation and stability. However, elucidating the function of this receptor in this range of settings is challenging since MuSK participates in at least three signaling pathways: as a tyrosine kinase-dependent receptor for agrin-LRP4 and Wnts; and, as a kinase-independent BMP co-receptor. Here we focus on NMJ stability during aging and discuss open questions regarding the molecular mechanisms that govern active maintenance of the NMJ, with emphasis on MuSK and the potential role of its multiple signaling contexts.
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15
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Vogt J, Al-Saedi A, Willis T, Male A, McKie A, Kiely N, Maher ER. A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome-related disorders. Clin Genet 2020; 97:908-914. [PMID: 32092148 DOI: 10.1111/cge.13728] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/28/2020] [Accepted: 02/16/2020] [Indexed: 12/24/2022]
Abstract
Multiple pterygium syndrome (MPS) disorders are a phenotypically and genetically heterogeneous group of conditions characterized by multiple joint contractures (arthrogryposis), pterygia (joint webbing) and other developmental defects. MPS is most frequently inherited in an autosomal recessive fashion but X-linked and autosomal dominant forms also occur. Advances in genomic technologies have identified many genetic causes of MPS-related disorders and genetic diagnosis requires large targeted next generation sequencing gene panels or genome-wide sequencing approaches. Using the Illumina TruSightOne clinical exome assay, we identified a recurrent heterozygous missense substitution in TPM2 (encoding beta tropomyosin) in three unrelated individuals. This was confirmed to have arisen as a de novo event in the two patients with parental samples. TPM2 mutations have previously been described in association with a variety of dominantly inherited neuromuscular phenotypes including nemaline myopathy, congenital fibre-type disproportion, distal arthrogryposis and trismus pseudocamptodactyly, and in a patient with autosomal recessive Escobar syndrome and a nemaline myopathy. The three cases reported here had overlapping but variable features. Our findings expand the range of TMP2-related phenotypes and indicate that de novo TMP2 mutations should be considered in isolated cases of MPS-related conditions.
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Affiliation(s)
- Julie Vogt
- West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK
| | - Atif Al-Saedi
- Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham, UK
| | - Tracey Willis
- Neuromuscular Service, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
| | - Alison Male
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Arthur McKie
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Nigel Kiely
- Neuromuscular Service, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
| | - Eamonn R Maher
- Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham, UK.,Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
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16
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Herbst R. MuSk function during health and disease. Neurosci Lett 2019; 716:134676. [PMID: 31811897 DOI: 10.1016/j.neulet.2019.134676] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/02/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023]
Abstract
The receptor tyrosine kinase MuSK (muscle-specific kinase) is the key signaling molecule during the formation of a mature and functional neuromuscular junction (NMJ). Signal transduction events downstream of MuSK activation induce both pre- and postsynaptic differentiation, which, most prominently, includes the clustering of acetylcholine receptors (AChRs) at synaptic sites. MuSK activation requires a complex interplay between its co-receptor Lrp4 (low-density lipoprotein receptor-related protein-4), the motor neuron-derived heparan-sulfate proteoglycan Agrin and the intracellular adaptor protein Dok-7. A tight regulation of MuSK kinase activity is crucial for proper NMJ development. Defects in MuSK signaling are the cause of muscle weakness as reported in congenital myasthenic syndromes and myasthenia gravis. This review focuses on recent structure-based analyses of MuSK, Agrin, Lrp4 and Dok-7 interactions and their function during MuSK activation. Conclusions about the regulation of the MuSK kinase that were derived from molecular structures will be highlighted. In addition, the role of MuSK during development and disease will be discussed.
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Affiliation(s)
- Ruth Herbst
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Kinderspitalgasse 15, 1090 Vienna, Austria.
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17
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Li N, Qiao C, Lv Y, Yang T, Liu H, Yu WQ, Liu CX. Compound heterozygous mutation of MUSK causing fetal akinesia deformation sequence syndrome: A case report. World J Clin Cases 2019; 7:3655-3661. [PMID: 31750350 PMCID: PMC6854405 DOI: 10.12998/wjcc.v7.i21.3655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 08/23/2019] [Accepted: 09/09/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Fetal akinesia deformation sequence (FADS) is a broad spectrum disorder with absent fetal movements as the unifying feature. The etiology of FADS is heterogeneous and mostly still unknown. A prenatal diagnosis of FADS relies on clinical features obtained by ultrasound and fetal muscle pathology. However, the recent advances of next-generation sequencing (NGS) can effectively provide a definitive molecular diagnosis.
CASE SUMMARY A fetus presented after 24 wk and 6 d of gestation with absent fetal movements and multiple abnormal ultrasonographic signs. The mother had had a previous abortion due to a similarly affected fetus a year before. A clinical diagnosis of FADS was made. The parents refused cord blood examination and chose abortion. A molecular diagnosis of fetal muscle using NGS of genes found a compound heterozygous mutation in the MUSK gene: c.220C > T (chr9: 113449410 p.R74W) and c.421delC (chr9: 113457745 p.P141fs).
CONCLUSION To our knowledge, this is the first report in China showing that a mutation in MUSK is associated with FADS. This supports previous finding that a lethal mutation of MUSK will cause FADS. A precise molecular diagnosis for genetic counseling and options for a prenatal diagnosis of FADS are very important, especially for recurrent FADS; this may also provide evidence for both prenatal and preimplantation genetic diagnoses.
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Affiliation(s)
- Na Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Chong Qiao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Yuan Lv
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Tian Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Hao Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Wen-Qian Yu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
| | - Cai-Xia Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang 110004, Liaoning Province, China
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18
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Niles KM, Blaser S, Shannon P, Chitayat D. Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)-Aetiology, diagnosis, and management. Prenat Diagn 2019; 39:720-731. [PMID: 31218730 DOI: 10.1002/pd.5505] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/21/2019] [Accepted: 06/04/2019] [Indexed: 01/01/2023]
Abstract
Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.
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Affiliation(s)
- Kirsten M Niles
- Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Susan Blaser
- Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada
| | - Patrick Shannon
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - David Chitayat
- Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.,The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.,Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, ON, Canada
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19
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Cáceres JJ, Paccanaro A. Disease gene prediction for molecularly uncharacterized diseases. PLoS Comput Biol 2019; 15:e1007078. [PMID: 31276496 PMCID: PMC6636748 DOI: 10.1371/journal.pcbi.1007078] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 07/17/2019] [Accepted: 05/09/2019] [Indexed: 02/06/2023] Open
Abstract
Network medicine approaches have been largely successful at increasing our knowledge of molecularly characterized diseases. Given a set of disease genes associated with a disease, neighbourhood-based methods and random walkers exploit the interactome allowing the prediction of further genes for that disease. In general, however, diseases with no known molecular basis constitute a challenge. Here we present a novel network approach to prioritize gene-disease associations that is able to also predict genes for diseases with no known molecular basis. Our method, which we have called Cardigan (ChARting DIsease Gene AssociatioNs), uses semi-supervised learning and exploits a measure of similarity between disease phenotypes. We evaluated its performance at predicting genes for both molecularly characterized and uncharacterized diseases in OMIM, using both weighted and binary interactomes, and compared it with state-of-the-art methods. Our tests, which use datasets collected at different points in time to replicate the dynamics of the disease gene discovery process, prove that Cardigan is able to accurately predict disease genes for molecularly uncharacterized diseases. Additionally, standard leave-one-out cross validation tests show how our approach outperforms state-of-the-art methods at predicting genes for molecularly characterized diseases by 14%-65%. Cardigan can also be used for disease module prediction, where it outperforms state-of-the-art methods by 87%-299%.
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Affiliation(s)
- Juan J. Cáceres
- Centre for Systems and Synthetic Biology & Department of Computer Science, Royal Holloway, University of London, Egham, Surrey, United Kingdom
| | - Alberto Paccanaro
- Centre for Systems and Synthetic Biology & Department of Computer Science, Royal Holloway, University of London, Egham, Surrey, United Kingdom
- * E-mail:
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20
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Lukacs M, Gilley J, Zhu Y, Orsomando G, Angeletti C, Liu J, Yang X, Park J, Hopkin RJ, Coleman MP, Zhai RG, Stottmann RW. Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence. Exp Neurol 2019; 320:112961. [PMID: 31136762 DOI: 10.1016/j.expneurol.2019.112961] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 10/26/2022]
Abstract
The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and hydrops fetalis. Clinical exome sequencing identified compound heterozygous NMNAT2 variant alleles in both cases. Both protein variants are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein stability and/or defects in NAD+ synthesis and chaperone functions. Thus, both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder. SIGNIFICANCE: Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) both synthesizes the electron carrier Nicotinamide Adenine Dinucleotide (NAD+) and acts a protein chaperone. NMNAT2 has emerged as a major neuron survival factor. Overexpression of NMNAT2 protects neurons from Wallerian degeneration after injury and declining levels of NMNAT2 have been implicated in neurodegeneration. While the role of NMNAT2 in neurodegeneration has been extensively studied, the role of NMNAT2 in human development remains unclear. In this work, we present the first human variants in NMNAT2 identified in two fetuses with severe skeletal muscle hypoplasia and fetal akinesia. Functional studies in vitro showed that the mutations impair both NMNAT2 NAD+ synthase and chaperone functions. This work identifies the critical role of NMNAT2 in human development.
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Affiliation(s)
- Marshall Lukacs
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA..
| | - Jonathan Gilley
- John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.; Signalling ISPG, The Babraham Institute, Babraham, Cambridge CB22 3AT, UK.
| | - Yi Zhu
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Giuseppe Orsomando
- Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131, Ancona, Italy.
| | - Carlo Angeletti
- Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131, Ancona, Italy.
| | - Jiaqi Liu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China.
| | - Xiuna Yang
- John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK
| | - Joun Park
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Robert J Hopkin
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA..
| | - Michael P Coleman
- John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.; Signalling ISPG, The Babraham Institute, Babraham, Cambridge CB22 3AT, UK.
| | - R Grace Zhai
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China.
| | - Rolf W Stottmann
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA..
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21
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Jia C, Wang H, Li C, Wu X, Zan L, Ding X, Guo X, Bao P, Pei J, Chu M, Liang C, Yan P. Genome-wide detection of copy number variations in polled yak using the Illumina BovineHD BeadChip. BMC Genomics 2019; 20:376. [PMID: 31088363 PMCID: PMC6518677 DOI: 10.1186/s12864-019-5759-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/02/2019] [Indexed: 01/29/2023] Open
Abstract
Background Copy number variations (CNVs), which are genetic variations present throughout mammalian genomes, are a vital source of phenotypic variation that can lead to the development of unique traits. In this study we used the Illunima BovineHD BeadChip to conduct genome-wide detection of CNVs in 215 polled yaks. Results A total of 1066 CNV regions (CNVRs) were detected with a total length of 181.6 Mb, comprising ~ 7.2% of the bovine autosomal genome. The size of these CNVRs ranged from 5.53 kb to 1148.45 kb, with an average size of 170.31 kb. Eight out of nine randomly chosen CNVRs were successfully validated by qPCR. A functional enrichment analysis of the CNVR-associated genes indicated their relationship to a number of molecular adaptations that enable yaks to thrive at high altitudes. One third of the detected CNVRs were mapped to QTLs associated with six classes of economically important traits, indicating that these CNVRs may play an important role in variations of these traits. Conclusions Our genome-wide yak CNV map may thus provide valuable insights into both the molecular mechanisms of high altitude adaptation and the potential genomic basis of economically important traits in yak. Electronic supplementary material The online version of this article (10.1186/s12864-019-5759-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Congjun Jia
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China.,College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Hongbo Wang
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Chen Li
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Xiaoyun Wu
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Linsen Zan
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xuezhi Ding
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Xian Guo
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Pengjia Bao
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Jie Pei
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Min Chu
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
| | - Chunnian Liang
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China.
| | - Ping Yan
- Key Laboratory of Yak Breeding Engineering Gansu Province, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China.
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22
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Kalınlı M, Ekinci Ö, Güneş S, Ekinci N. Autistic-Like Traits in Pena-Shokeir Syndrome. J Autism Dev Disord 2019; 49:1316-1318. [PMID: 30430318 DOI: 10.1007/s10803-018-3824-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Pena-Shokeir syndrome (PSS) is a rare, early lethal disease. PSS is characterized by fetal growth restriction, craniofacial deformities, multiple ankyloses and pulmonary hypoplasia. Because of the primary concern of physical health problems, psychiatric evaluation is frequently underestimated in PSS patients. Our case report describes a child with PSS who presented with autistic spectrum disorder symptoms.
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Affiliation(s)
- Merve Kalınlı
- Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.
| | - Özalp Ekinci
- Department of Child and Adolescent Psychiatry, University of Health Sciences Medical Faculty, Istanbul, Turkey
| | - Serkan Güneş
- Department of Child and Adolescent Psychiatry, Antakya State Hospital, Hatay, Turkey
| | - Nuran Ekinci
- Department of Child and Adolescent Psychiatry, University of Health Sciences Medical Faculty, Istanbul, Turkey
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23
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Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence. PLoS Genet 2018; 14:e1007845. [PMID: 30543681 PMCID: PMC6307818 DOI: 10.1371/journal.pgen.1007845] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/27/2018] [Accepted: 11/20/2018] [Indexed: 12/20/2022] Open
Abstract
Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS. Fetal movement is a prerequisite for normal fetal development and growth. Fetal akinesia deformation sequence (FADS) is the result of decreased fetal movement coinciding with congenital malformations related to impaired fetal movement. FADS may be caused by heterogenous defects at any point along the motor system pathway and genes encoding components critical to the neuromuscular junction and acetylcholine receptor clustering represent a major class of FADS disease genes. We report here biallelic, loss-of-function mutations in the nucleoporin NUP88 that result in lethal FADS and with this the first lethal human developmental disorder due to mutations in a nucleoporin gene. We show that loss of Nup88 in zebrafish results in defects reminiscent of those seen in affected human fetuses and loss of NUP88 affects distinct developmental stages, both during human and zebrafish development. Consistent with the notion that a primary cause for FADS is impaired formation of the neuromuscular junction, loss of Nup88 in zebrafish coincides with abnormalities in acetylcholine receptor clustering, suggesting that defective NUP88 function in FADS impairs neuromuscular junction formation.
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24
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Adam S, Coetzee M, Honey EM. Pena-Shokeir syndrome: current management strategies and palliative care. APPLICATION OF CLINICAL GENETICS 2018; 11:111-120. [PMID: 30498368 PMCID: PMC6207248 DOI: 10.2147/tacg.s154643] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pena-Shokeir syndrome (PSS) type 1, also known as fetal akinesia deformation sequence, is a rare genetic syndrome that almost always results in intrauterine or early neonatal death. It is characterized by markedly decreased fetal movements, intrauterine growth restriction, joint contractures, short umbilical cord, and features of pulmonary hypoplasia. Antenatal diagnosis can be difficult. Ultrasound features are varied and may overlap with those of Trisomy 18. The poor prognosis of PSS is due to pulmonary hypoplasia, which is an important feature that distinguishes PSS from arthrogryposis multiplex congenital without pulmonary hypoplasia, which has a better prognosis. If diagnosed in the antenatal period, a late termination of pregnancy can be considered following ethical discussion (if the law allows). In most cases, a diagnosis is only made in the neonatal period. Parents of a baby affected with PSS require detailed counseling that includes information on the imprecise recurrence risks and a plan for subsequent pregnancies.
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Affiliation(s)
- Sumaiya Adam
- Department of Obstetrics and Gynaecology, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa,
| | - Melantha Coetzee
- Division of Neonatology, Department of Pediatrics and Child Health, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Engela Magdalena Honey
- Department of Biochemistry, Genetics and Microbiology, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, South Africa
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25
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Beecroft SJ, Lombard M, Mowat D, McLean C, Cairns A, Davis M, Laing NG, Ravenscroft G. Genetics of neuromuscular fetal akinesia in the genomics era. J Med Genet 2018; 55:505-514. [PMID: 29959180 DOI: 10.1136/jmedgenet-2018-105266] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/22/2018] [Accepted: 04/19/2018] [Indexed: 12/27/2022]
Abstract
Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next-generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle.
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Affiliation(s)
- Sarah Jane Beecroft
- Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia
| | - Marcus Lombard
- Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia
| | - David Mowat
- Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia
| | - Catriona McLean
- Victorian Neuromuscular Laboratory, Alfred Health, Melbourne, Victoria, Australia
| | - Anita Cairns
- Department of Neurology, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
| | - Mark Davis
- Neurogenetics Laboratory, Department of Diagnostic Genomics, PP Block, QEII Medical Centre, Nedlands, Western Australia, Australia
| | - Nigel G Laing
- Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia
| | - Gianina Ravenscroft
- Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia
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26
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Stattin EL, Johansson J, Gudmundsson S, Ameur A, Lundberg S, Bondeson ML, Wilbe M. A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases. Am J Med Genet A 2018; 176:1405-1410. [PMID: 29663639 DOI: 10.1002/ajmg.a.38691] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/20/2018] [Accepted: 03/11/2018] [Indexed: 12/11/2022]
Abstract
Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.
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Affiliation(s)
- Eva-Lena Stattin
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Josefin Johansson
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Sanna Gudmundsson
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Adam Ameur
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Staffan Lundberg
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Marie-Louise Bondeson
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Maria Wilbe
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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27
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With expanded carrier screening, founder populations run the risk of being overlooked. J Community Genet 2017; 8:327-333. [PMID: 28555434 PMCID: PMC5614881 DOI: 10.1007/s12687-017-0309-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 05/16/2017] [Indexed: 11/25/2022] Open
Abstract
Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations. We investigated whether these founder mutations are covered in the (preconception) expanded carrier screening tests of five carrier screening providers. Our results show that the great majority of founder mutations are not covered in these screening panels, and these panels may thus not be appropriate for use in founder populations. It is therefore important to be aware of founder mutations in a population when offering carrier tests.
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28
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Shpakov AO, Zharova OA, Derkach KV. Antibodies to extracellular regions of G protein-coupled receptors and receptor tyrosine kinases as one of the causes of autoimmune diseases. J EVOL BIOCHEM PHYS+ 2017. [DOI: 10.1134/s1234567817020021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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29
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Prenatal diagnosis of fetal akinesia deformation sequence (FADS): a study of 79 consecutive cases. Arch Gynecol Obstet 2016; 294:697-707. [DOI: 10.1007/s00404-016-4017-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 01/05/2016] [Indexed: 10/22/2022]
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30
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Bayram Y, Karaca E, Coban Akdemir Z, Yilmaz EO, Tayfun GA, Aydin H, Torun D, Bozdogan ST, Gezdirici A, Isikay S, Atik MM, Gambin T, Harel T, El-Hattab AW, Charng WL, Pehlivan D, Jhangiani SN, Muzny DM, Karaman A, Celik T, Yuregir OO, Yildirim T, Bayhan IA, Boerwinkle E, Gibbs RA, Elcioglu N, Tuysuz B, Lupski JR. Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. J Clin Invest 2016; 126:762-78. [PMID: 26752647 DOI: 10.1172/jci84457] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/25/2015] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.
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31
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Todd EJ, Yau KS, Ong R, Slee J, McGillivray G, Barnett CP, Haliloglu G, Talim B, Akcoren Z, Kariminejad A, Cairns A, Clarke NF, Freckmann ML, Romero NB, Williams D, Sewry CA, Colley A, Ryan MM, Kiraly-Borri C, Sivadorai P, Allcock RJN, Beeson D, Maxwell S, Davis MR, Laing NG, Ravenscroft G. Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth. Orphanet J Rare Dis 2015; 10:148. [PMID: 26578207 PMCID: PMC4650299 DOI: 10.1186/s13023-015-0364-0] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/02/2015] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Fetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual's DNA can now be analysed through "whole" exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these. METHODS Genomic DNA samples from 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated families were subjected to next generation sequencing. Clinical features and diagnoses for each patient were supplied by referring clinicians. Genomic DNA was used for either whole exome sequencing or a custom-designed neuromuscular sub-exomic supercapture array containing 277 genes responsible for various neuromuscular diseases. Candidate disease-causing variants were investigated and confirmed using Sanger sequencing. Some of the cases within this cohort study have been published previously as separate studies. RESULTS A conclusive genetic diagnosis was achieved for 18 of the 38 families. Within this cohort, mutations were found in eight previously known neuromuscular disease genes (CHRND, CHNRG, ECEL1, GBE1, MTM1, MYH3, NEB and RYR1) and four novel neuromuscular disease genes were identified and have been published as separate reports (GPR126, KLHL40, KLHL41 and SPEG). In addition, novel mutations were identified in CHRND, KLHL40, NEB and RYR1. Autosomal dominant, autosomal recessive, X-linked, and de novo modes of inheritance were observed. CONCLUSIONS By using next generation sequencing on a cohort of 38 unrelated families with fetal akinesia/hypokinesia, arthrogryposis, or severe congenital myopathy we therefore obtained a genetic diagnosis for 47% of families. This study highlights the power and capacity of next generation sequencing (i) to determine the aetiology of genetically heterogeneous neuromuscular diseases, (ii) to identify novel disease genes in small pedigrees or isolated cases and (iii) to refine the interplay between genetic diagnosis and clinical evaluation and management.
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Affiliation(s)
- Emily J Todd
- Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands, 6009, , WA, Australia.
| | - Kyle S Yau
- Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands, 6009, , WA, Australia.
| | - Royston Ong
- Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands, 6009, , WA, Australia.
| | - Jennie Slee
- Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, 6000, , WA, Australia.
| | - George McGillivray
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, 3052, , VIC, Australia.
| | - Christopher P Barnett
- Paediatric and Reproductive Genetics Unit, South Australia Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, 5006, , SA, Australia.
| | - Goknur Haliloglu
- Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, 06100, Turkey.
| | - Beril Talim
- Pediatric Pathology Unit, Hacettepe University Children's Hospital, Ankara, 06100, Turkey.
| | - Zuhal Akcoren
- Pediatric Pathology Unit, Hacettepe University Children's Hospital, Ankara, 06100, Turkey.
| | - Ariana Kariminejad
- Kariminejad-Najmabadi Pathology and Genetics Centre, Tehran, 14656, Iran.
| | - Anita Cairns
- Royal Children's Hospital, Herston Road, Herson, 4029, , QLD, Australia.
| | - Nigel F Clarke
- Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, 2145, , NSW, Australia. .,Discipline of Paediatrics and Child Health, University of Sydney, Sydney, 2006, , NSW, Australia.
| | | | - Norma B Romero
- Unitè de Morphologie Neuromusculaire, Institut de Myologie, Institut National de la Santè et de la Recherche Mèdicale, Paris, 75651, France.
| | - Denise Williams
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK. .,Wolfson Centre for Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK.
| | - Caroline A Sewry
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, WC1N 1EH, UK. .,Wolfson Centre for Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK.
| | - Alison Colley
- Department of Clinical Genetics, South Western Sydney Local Health District, Liverpool, 1871, , NSW, Australia.
| | - Monique M Ryan
- Department of Neurology, The Royal Children's Hospital, Melbourne, 3000, , VIC, Australia.
| | - Cathy Kiraly-Borri
- Genetic Services of Western Australia, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Subiaco, 6008, , WA, Australia.
| | - Padma Sivadorai
- Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, 6009, , WA, Australia.
| | - Richard J N Allcock
- Lotterywest State Biomedical Facility Genomics and School of Pathology and Laboratory Medicine, University of Western Australia, Perth, 6000, , WA, Australia.
| | - David Beeson
- Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
| | - Susan Maxwell
- Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
| | - Mark R Davis
- Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, 6009, , WA, Australia.
| | - Nigel G Laing
- Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands, 6009, , WA, Australia. .,Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, 6009, , WA, Australia.
| | - Gianina Ravenscroft
- Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, QQ Block, 6 Verdun Street, Nedlands, 6009, , WA, Australia.
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Bronicki LM, Stevenson RE, Spranger JW. Beyond osteogenesis imperfecta: Causes of fractures during infancy and childhood. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2015; 169:314-27. [PMID: 26531771 DOI: 10.1002/ajmg.c.31466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Fractures in infancy or early childhood require prompt evaluation with consideration of accidental or non-accidental trauma as well as a large number of genetic disorders that predispose to fractures. Bone fragility has been reported in more than 100 genetic disorders, including skeletal dysplasias, inborn errors of metabolism and congenital insensitivity to pain. Most of these disorders are rare but often have distinctive clinical or radiographic findings to assist in the diagnosis. Gene sequencing is available, albeit connective tissue and skeletal dysplasia panels and biochemical studies are only helpful in a minority of cases. This article presents the clinical, radiographic, and molecular profiles of the most common heritable disorders other than osteogenesis imperfecta with increased bone fragility. In addition, the clinicians must consider non-heritable influences such as extreme prematurity, prenatal viral infection and neoplasia in the diagnostic process.
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Mathijssen IB, Henneman L, van Eeten-Nijman JMC, Lakeman P, Ottenheim CPE, Redeker EJW, Ottenhof W, Meijers-Heijboer H, van Maarle MC. Targeted carrier screening for four recessive disorders: high detection rate within a founder population. Eur J Med Genet 2015; 58:123-8. [PMID: 25641760 DOI: 10.1016/j.ejmg.2015.01.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 01/07/2015] [Indexed: 12/13/2022]
Abstract
In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general population.
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Affiliation(s)
- Inge B Mathijssen
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
| | - Lidewij Henneman
- Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
| | | | - Phillis Lakeman
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
| | - Cecile P E Ottenheim
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
| | - Egbert J W Redeker
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
| | - Winnie Ottenhof
- Waterland Oost Midwifery Practice, Volendam, The Netherlands
| | - Hanne Meijers-Heijboer
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
| | - Merel C van Maarle
- Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
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