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1
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Bea-Mascato B, Valverde D. Genotype-phenotype associations in Alström syndrome: a systematic review and meta-analysis. J Med Genet 2023; 61:18-26. [PMID: 37321834 PMCID: PMC10803979 DOI: 10.1136/jmg-2023-109175] [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: 01/20/2023] [Accepted: 05/29/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Alström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the ALMS1 gene, which encodes a centrosome-associated protein involved in the regulation of several ciliary and extraciliary processes, such as centrosome cohesion, apoptosis, cell cycle control and receptor trafficking. The type of variant associated with ALMS is mostly complete loss-of-function variants (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with limited success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study. METHODS In this study we collected all cases of ALMS published to date. We created a database of patients who had a genetic diagnosis and an individualised clinical history. Lastly, we attempted to establish a genotype-phenotype correlation using the truncation site of the patient's longest allele as a grouping criteria. RESULTS We collected a total of 357 patients, of whom 227 had complete clinical information, complete genetic diagnosis and meta-information on sex and age. We have seen that there are five variants with high frequency, with p.(Arg2722Ter) being the most common variant, with 28 alleles. No gender differences in disease progression were detected. Finally, truncating variants in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS. CONCLUSION Pathogenic variants in exon 10 of the ALMS1 gene were associated with a higher prevalence of liver disease. However, the location of the variant in the ALMS1 gene does not have a major impact on the phenotype developed by the patient.
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Affiliation(s)
- Brais Bea-Mascato
- CINBIO, Universidad de Vigo, 36310 Vigo, Spain
- Grupo de Investigación en Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
| | - Diana Valverde
- CINBIO, Universidad de Vigo, 36310 Vigo, Spain
- Grupo de Investigación en Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
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Xu R, Zhou H, Fang F, Qiu L, Liu X. A novel variant site of Alstrom syndrome in a Chinese child: a case report. Transl Pediatr 2022; 11:595-600. [PMID: 35558973 PMCID: PMC9085953 DOI: 10.21037/tp-21-535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/24/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem dysfunction, displaying unique clinical signs and symptoms and various severity, which may lead to delayed prognosis or misdiagnosis in medical practice. Although almost 300 pathogenic variants have been reported, there are some variant sites that have not been recognized yet. CASE DESCRIPTION We report a case of a 14-year-old boy with manifestations, including binocular vision loss, acanthosis nigricans, type 2 diabetes, insulin resistance, elevated transaminase, hepatic fibrosis, and proteinuria. Compound heterozygous variants in the ALMS1 gene have been discovered by whole exon sequencing. One of his variant sites was C. 8158C>T, which was from his father. And the other variant site was C. 3575C>A, which was from his mother. To the great of our knowledge, this site has not been reported before. Both of the variants make the synthesis of the peptide chain terminated in advance and an incomplete polypeptide chain is formed. CONCLUSIONS The clinical presentations of ALMS are complicated and varied. Although early diagnosis can be made according to typical clinical symptoms, whole exon sequencing is necessary for the diagnosis of ALMS, as indicated by our study.
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Affiliation(s)
- Rongrong Xu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Zhou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Fang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liru Qiu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinglou Liu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhang JJ, Wang JQ, Sun MQ, Xu D, Xiao Y, Lu WL, Dong ZY. Alström syndrome with a novel mutation of ALMS1 and Graves’ hyperthyroidism: A case report and review of the literature. World J Clin Cases 2021; 9:3200-3211. [PMID: 33969109 PMCID: PMC8080750 DOI: 10.12998/wjcc.v9.i13.3200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/21/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alström syndrome (AS, OMIM ID 203800) is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients. In the Chinese population, there are few reports on the clinical manifestations and pathogenesis of AS. This is the first report on the association between AS and Graves’ hyperthyroidism.
CASE SUMMARY An 8-year-old Chinese girl was diagnosed with AS. Two years later, Graves’ hyperthyroidism developed with progressive liver dysfunction. The patient’s clinical data were collected; DNA from peripheral blood of the proband, parents and sibling was collected for gene mutation detection using the second-generation sequencing method and gene panel for diabetes. The association between the patient’s genotype and clinical phenotype was analyzed. She carried the pathogenic compound heterozygous mutation of ALMS1 (c.2296_2299del4 and c.11460C>A). These stop-gain mutations likely caused truncation of the ALMS1 protein.
CONCLUSION The manifestation of hyperthyroidism may suggest rapid progression of AS.
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Affiliation(s)
- Juan-Juan Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Jun-Qi Wang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Man-Qing Sun
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - De Xu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Yuan Xiao
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Wen-Li Lu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
| | - Zhi-Ya Dong
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University, School of Medicine, Shanghai 200025, China
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Zaveri MP, Perry JC, Schuetz TM, Memon MD, Faiz S, Cancarevic I. Diabetic Cardiomyopathy as a Clinical Entity: Is It a Myth? Cureus 2020; 12:e11100. [PMID: 33240696 PMCID: PMC7681757 DOI: 10.7759/cureus.11100] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy that affects the cardiac muscle. It is a life-threatening condition that causes heart failure as it decreases the myocardial ability to pump sufficient blood throughout the body. Numerous causes trigger DCM without pathophysiology; however, the key concept is a decrease in the systolic function of either the left ventricle or of both the left and right ventricles. Long-term diabetes plays an important role in the pathogenesis of DCM in the form of diabetic cardiomyopathy. Diabetic cardiomyopathy is a non-ischemic form of DCM, which is associated with diabetes. It is unrelated to atherosclerosis and hypertension. The PubMed and Google Scholar databases were used to identify the relevant studies related to diabetes and DCM. We found that diabetes was associated with cardiac muscle injury by activating the renin-angiotensin-aldosterone system, myocardial inflammation, and fibrosis. Based on the available data, we concluded that there is strong evidence to support the interrelation of DCM and diabetes.
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Affiliation(s)
- Mitul P Zaveri
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Jamal C Perry
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Tayná M Schuetz
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammad D Memon
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sadaf Faiz
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ivan Cancarevic
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Kılınç S, Yücel-Yılmaz D, Ardagil A, Apaydın S, Valverde D, Özgül RK, Güven A. Five novel ALMS1 gene mutations in six patients with Alström syndrome. J Pediatr Endocrinol Metab 2018; 31:681-687. [PMID: 29715191 DOI: 10.1515/jpem-2017-0418] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 03/12/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. METHODS We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition. RESULTS Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously. CONCLUSIONS Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.
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Affiliation(s)
- Suna Kılınç
- Department of Pediatric Endocrinology, Göztepe Education and Research Hospital, Pediatric Endocrinology Clinic, Istanbul, Turkey
| | - Didem Yücel-Yılmaz
- Hacettepe University, Institute of Child Health, Department of Pediatric Metabolism, Ankara, Turkey
| | - Aylin Ardagil
- Department of Ophthalmology, Göztepe Education and Research Hospital, Ophthalmology Clinics, Istanbul, Turkey
| | - Süheyla Apaydın
- Department of Nephrology, Nephrologist, Bakirkoy Sadi Konuk Education and Research Hospital, Nephrology Clinics, Istanbul, Turkey
| | - Diana Valverde
- Departamento de Bioquímica, Genética e Inmunología, Facultad de Biología, Universidad de Vigo, Pontevedra, Spain
| | - Rıza Köksal Özgül
- Hacettepe University, Institute of Child Health, Department of Pediatric Metabolism, Ankara, Turkey
| | - Ayla Güven
- Zeynep Kamil Kadın ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi, Dr. Burhanettin Üstünel sokak, 34668, Üsküdar, Istanbul, Turkey, Phone: +905322380300
- Pediatric Endocrinologist, Göztepe Education and Research Hospital, Pediatric Endocrinology Clinic, Istanbul, Turkey
- Amasya University Medical Faculty, Department of Pediatrics, Amasya, Turkey
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6
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Govil M, Mukhopadhyay N, Weeks DE, Feingold E, Shaffer JR, Levy SM, Vieira AR, Slayton RL, McNeil DW, Weyant RJ, Crout RJ, Marazita ML. Novel caries loci in children and adults implicated by genome-wide analysis of families. BMC Oral Health 2018; 18:98. [PMID: 29859070 PMCID: PMC5984765 DOI: 10.1186/s12903-018-0559-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 05/22/2018] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Dental caries is a common chronic disease among children and adults alike, posing a substantial health burden. Caries is affected by multiple genetic and environmental factors, and prior studies have found that a substantial proportion of caries susceptibility is genetically inherited. METHODS To identify such genetic factors, we conducted a genome-wide linkage scan in 464 extended families with 2616 individuals from Iowa, Pennsylvania and West Virginia for three dental caries phenotypes: (1) PRIM: dichotomized as zero versus one or more affected primary teeth, (2) QTOT1: age-adjusted quantitative caries measure for both primary and permanent dentitions including pre-cavitated lesions, and (3) QTOT2: age-adjusted quantitative caries excluding pre-cavitated lesions. Genotyping was conducted for approximately 600,000 SNPs on an Illumina platform, pruned to 127,511 uncorrelated SNPs for the analyses reported here. RESULTS Multipoint non-parametric linkage analyses generated peak LOD scores exceeding 2.0 for eight genomic regions, but no LOD scores above 3.0 were observed. The maximum LOD score for each of the three traits was 2.90 at 1q25.3 for PRIM, 2.38 at 6q25.3 for QTOT1, and 2.76 at 5q23.3 for QTOT2. Some overlap in linkage regions was observed among the phenotypes. Genes with a potential role in dental caries in the eight chromosomal regions include CACNA1E, LAMC2, ALMS1, STAMBP, GXYLT2, SLC12A2, MEGF10, TMEM181, ARID1B, and, as well as genes in several immune gene families. Our results are also concordant with previous findings from association analyses on chromosomes 11 and 19. CONCLUSIONS These multipoint linkage results provide evidence in favor of novel chromosomal regions, while also supporting earlier association findings for these data. Understanding the genetic etiology of dental caries will allow designing personalized treatment plans based on an individual's genetic risk of disease.
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Affiliation(s)
- Manika Govil
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
| | - Nandita Mukhopadhyay
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
| | - Daniel E. Weeks
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
| | - Eleanor Feingold
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
| | - John R. Shaffer
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
| | - Steven M. Levy
- Department of Preventive and Community Dentistry, University of Iowa College of Dentistry, Iowa City, IA USA
- Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA USA
| | - Alexandre R. Vieira
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
| | - Rebecca L. Slayton
- Department of Pediatric Dentistry, School of Dentistry, University of Washington, Seattle, WA USA
| | - Daniel W. McNeil
- Dental Practice and Rural Health, West Virginia University School of Dentistry, Morgantown, WV USA
- Department of Psychology, Eberly College of Arts and Sciences, West Virginia University, Morgantown, WV USA
| | - Robert J. Weyant
- Department of Dental Public Health and Information Management, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA USA
| | - Richard J. Crout
- Department of Periodontics, West Virginia University School of Dentistry, Morgantown, WV USA
| | - Mary L. Marazita
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500 Bridgeside Point, 100 Technology Drive, Pittsburgh, PA 15219 USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA
- Clinical and Translational Science Institute, and Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
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7
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Paisey RB, Leeson-Beevers K. Current management of Alström syndrome and recent advances in treatment. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2016.1189322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- R. B. Paisey
- Diabetes Research, Horizon Centre, Torbay Hospital, Torquay, UK
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Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, Dinwiddie D, Farrow EG, Miller NA, Favaretto F, Maffei P, Dollfus H, Vettor R, Naggert JK. Alström Syndrome: Mutation Spectrum of ALMS1. Hum Mutat 2015; 36:660-8. [PMID: 25846608 PMCID: PMC4475486 DOI: 10.1002/humu.22796] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 03/25/2015] [Accepted: 03/29/2015] [Indexed: 12/24/2022]
Abstract
Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.
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Affiliation(s)
- Jan D. Marshall
- The Jackson Laboratory, Bar Harbor, Maine USA
- Alström Syndrome International, Mount Desert, ME USA
| | - Jean Muller
- IGBMC, CNRS UMR 7104/INSERM U964/University of Strasbourg, Illkirch Cedex, France
- Laboratoire ICUBE, UMR CNRS 7357, LBGI, Université de Strasbourg, Strasbourg, France
- Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg Cedex, France
| | | | | | - Stephen F. Kingsmore
- Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO
| | - Darrell Dinwiddie
- Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO
- Department of Pediatrics, University of New Mexico, Albuquerque, NM
| | - Emily G. Farrow
- Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO
| | - Neil A. Miller
- Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO
| | | | - Pietro Maffei
- Department of Medicine, University of Padua, Padua, Italy
| | - Hélène Dollfus
- Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, Strasbourg, France
- Service de Génétique Médicale, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Roberto Vettor
- Department of Medicine, University of Padua, Padua, Italy
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Ozantürk A, Marshall JD, Collin GB, Düzenli S, Marshall RP, Candan Ş, Tos T, Esen İ, Taşkesen M, Çayır A, Öztürk Ş, Üstün İ, Ataman E, Karaca E, Özdemir TR, Erol İ, Eroğlu FK, Torun D, Parıltay E, Yılmaz-Güleç E, Karaca E, Atabek ME, Elçioğlu N, Satman İ, Möller C, Muller J, Naggert JK, Özgül RK. The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey. J Hum Genet 2014; 60:1-9. [PMID: 25296579 DOI: 10.1038/jhg.2014.85] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/06/2014] [Accepted: 09/08/2014] [Indexed: 02/07/2023]
Abstract
Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.
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Affiliation(s)
- Ayşegül Ozantürk
- Institute of Child Health and Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | | | | | - Selma Düzenli
- Department of Medical Genetics, Abant İzzet Baysal University, Bolu, Turkey
| | | | - Şükrü Candan
- Department of Medical Genetics, Atatürk State Hospital, Balıkesir, Turkey
| | - Tülay Tos
- Dr. Sami Ulus Maternity and Children's Hospital, Ankara, Turkey
| | - İhsan Esen
- Ankara Pediatric Health and Hematology Oncology Hospital, Ankara,Turkey
| | | | - Atilla Çayır
- Pediatric Endocrinology Unit, Department of Medical Genetics, Atatürk University and Erzurum Regional Training and Research Hospital, Erzurum, Turkey
| | - Şükrü Öztürk
- Department of Medical Genetics, Istanbul Medical Faculty, İstanbul University, İstanbul, Turkey
| | - İhsan Üstün
- Department of Endocrinology, Mustafa Kemal University Hospital, Hatay, Turkey
| | - Esra Ataman
- Department of Medical Genetics, Ege University, İzmir, Turkey
| | - Emin Karaca
- 304;zmir Tepecik Training and Research Hospital Genetic Diagnostic Center, İzmir, Turkey
| | - Taha Reşid Özdemir
- 304;zmir Tepecik Training and Research Hospital Genetic Diagnostic Center, İzmir, Turkey
| | - İlknur Erol
- Division of Pediatric Neurology, Adana Teaching and Medical Research Center, Başkent University, Adana, Turkey
| | - Fehime Kara Eroğlu
- Nephrology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Deniz Torun
- Gülhane Military Medical Faculty, Department of Medical Genetics, Ankara, Turkey
| | - Erhan Parıltay
- Department of Medical Genetics, Ege University, İzmir, Turkey
| | - Elif Yılmaz-Güleç
- Kanuni Sultan Süleyman Training and Research Hospital, İstanbul, Turkey
| | - Ender Karaca
- Kanuni Sultan Süleyman Training and Research Hospital, İstanbul, Turkey
| | - M Emre Atabek
- Department of Pediatric Endocrinology, Necmettin Erbakan University, Konya, Turkey
| | - Nursel Elçioğlu
- Department of Pediatric Genetics, Marmara University Pendik Hospital, İstanbul, Turkey
| | - İlhan Satman
- Division of Endocrinology and Metabolism, İstanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey
| | - Claes Möller
- Department Audiology, The Swedish Institute for Disability Research, Örebro University Hospital, Örebro, Sweden
| | - Jean Muller
- 1] Laboratoire ICUBE, UMR CNRS 7357, LBGI, Université de Strasbourg, Strasbourg, France [2] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France [3] Laboratoire de diagnostic génétique, Hôtpitaux Universitaires de Strasbourg, Strasbourg, France
| | | | - Rıza Köksal Özgül
- Institute of Child Health and Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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10
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Sheck L, Al-Taie R, Sharp D, Vincent A. Alström syndrome--an uncommon cause of early childhood retinal dystrophy. BMJ Case Rep 2011; 2011:bcr.06.2011.4388. [PMID: 22688943 DOI: 10.1136/bcr.06.2011.4388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Alström syndrome (AS) is a ciliopathy and an uncommon cause of syndromic retinal dystrophy. This case reports findings in a 5-year-old boy with severe early onset retinal dystrophy, and how the recognition of extraocular features with genetic analysis led to the correct diagnosis of AS after 4 years of investigation.
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Affiliation(s)
- Leo Sheck
- Ophthalmology Department, University of Auckland, Auckland, New Zealand.
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Abstract
Genetic causes of obesity include the ciliopathies Alström syndrome and Bardet-Biedl syndrome. In these disorders, mutations cause dysfunction of the primary cilium, an organelle involved in intracellular and intercellular sensing and signaling. Alström syndrome is an autosomal-recessive disorder caused solely by mutations in ALMS1. By contrast, Bardet-Biedl syndrome is caused by mutations in at least 14 genes involved in primary cilium function. Despite equivalent levels of obesity, patients with Alström syndrome are more likely than those with Bardet-Biedl syndrome to develop childhood type 2 diabetes mellitus (T2DM), suggesting that ALMS1 might have a specific role in β-cell function and/or peripheral insulin signaling pathways. How mutations in genes that encode proteins involved in primary cilium function lead to the clinical phenotypes of these syndromes is being revealed by work in mutant mouse models. With the aid of these models, insights are being obtained into the pathogenic mechanisms that underlie obesity, insulin resistance and T2DM. Research into ciliopathies, including Alström syndrome and Bardet-Biedl syndrome, should lead not only to improved treatments for individuals with these genetic disorders, but also to improved understanding of the cellular pathways involved in other common causes of obesity and T2DM.
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Affiliation(s)
- Dorothée Girard
- Department of Endocrinology, Flinders Medical Center, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA 5042, Australia
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