A Nonsense ALMS1 Mutation Underlies Alström Syndrome in an Extended Mennonite Kindred Settled in North Mexico
Publication: Genetic Testing and Molecular Biomarkers
Volume 21, Issue Number 6
Abstract
Aim: Alström syndrome (AS) is a rare autosomal recessive multisystem disease caused by biallelic mutations in ALMS1, a gene encoding a widely expressed centrosomal/basal body protein. Although more than 200 pathogenic mutations in ALMS1 have been identified to date in AS patients from various ethnic populations, there are very few reports of ALMS1 founder mutations in isolated populations. Our aim was to describe the molecular characterization of a cohort of AS patients from an extended inbred Mennonite kindred settled in Mexico.
Methods: Genetic study included polymerase chain reaction amplification and direct nucleotide sequencing of the entire ALMS1 gene in DNA from seven related AS patients.
Results: A homozygous single-nucleotide c.10480C>T substitution in exon 16, predicting a p.Q3494* nonsense mutation, was identified in all affected subjects.
Conclusions: To our knowledge, this is the first demonstration of a high prevalence of AS in Mennonites, a population group maintaining high levels of consanguineous marriage in their communities. Our findings provide an example of genetic isolation and consanguinity causing a high prevalence of AS and offer the opportunity for early clinical interventions and for genetic counseling of at-risk couples in this community.
Get full access to this article
View all available purchase options and get full access to this article.
References
Alkuraya FS (2013) Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience. Clin Genet 84:203–208.
Alström CH, Hallgren B, Nilsson LB, Asander H (1959) Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence–Moon–Bardet–Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand 129 (Suppl):1–35.
Bettini V, Maffei P, Pagano C, et al. (2012) The progression from obesity to type 2 diabetes in Alström syndrome. Pediatr Diabetes 13:59–67.
Boycott KM, Parboosingh JS, Chodirker BN, et al. (2008) Clinical genetics and the Hutterite population: a review of Mendelian disorders. Am J Med Genet A 146A:1088–1098.
Collin GB, Cyr E, Bronson R, et al. (2005) Alms1-disrupted mice recapitulate human Alström syndrome. Hum Mol Genet 14:2323–2333.
Collin GB, Marshall JD, Ikeda A, et al. (2002) Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat Genet 31:74–78.
de Vries Y, Lwiwski N, Levitus M, et al. (2012) A Dutch Fanconi anemia FANCC founder mutation in Canadian Manitoba mennonites. Anemia 2012:865170.
Edwards NC, Moody WE, Yuan M, et al. (2015) Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study. Orphanet J Rare Dis 10:83.
Erzurumluoglu AM, Shihab HA, Rodriguez S, et al. (2016) Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions. Ann Hum Genet 80:187–196.
Girard D, Petrovsky N (2011) Alström syndrome: insights into the pathogenesis of metabolic disorders. Nat Rev Endocrinol 7:77–88.
Hearn T, Renforth GL, Spalluto C, et al. (2002) Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet 31:79–83.
Khoo EY, Risley J, Zaitoun AM, El-Sheikh M, et al. (2009) Alström syndrome and cecal volvulus in 2 siblings. Am J Med Sci 337:383–385.
Marshall JD, Beck S, Maffei P, Naggert JK (2007a) Alström syndrome. Eur J Hum Genet 15:1193–1202.
Marshall JD, Bronson RT, Collin GB, et al. (2005) New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 165:675–683.
Marshall JD, Hinman EG, Collin GB, et al. (2007b) Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Hum Mutat 28:1114–1123.
Marshall JD, Muller J, Collin GB, et al. (2015) Alström syndrome: mutation spectrum of ALMS1. Hum Mutat 36:660–668.
Marshall JD, Paisey RB, Carey C, Macdermott S (1993) Alström syndrome. In: Pagon RA, Adam MP, Ardinger HH et al. (eds) GeneReviews. University of Washington, Seattle. Updated May 31, 2012.
Minton JA, Owen KR, Ricketts CJ, et al. (2006) Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. J Clin Endocrinol Metab 91:3110–3116.
Orton NC, Innes AM, Chudley AE, Bech-Hansen NT (2008) Unique disease heritage of the Dutch-German Mennonite population. Am J Med Genet A 146A:1072–1087.
Paisey RB, Carey CM, Bower L, et al. (2004) Hypertriglyceridaemia in Alström's syndrome: causes and associations in 37 cases. Clin Endocrinol (Oxf) 60:228–231.
Puffenberger EG (2003) Genetic heritage of the old order Mennonites of southeastern Pennsylvania. Am J Med Genet C Semin Med Genet 121C:18–31.
Russell-Eggitt IM, Clayton PT, Coffey R, et al. (1998) Alström syndrome. Report of 22 cases and literature review. Ophthalmology 105:1274–1280.
Saunders-Pullman R, Raymond D, Stoessl AJ, et al. (2012) Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology 78:649–657.
Schroeder ML, Triggs-Raine B, Zelinski T (2016) Genotyping an immunodeficiency causing c.1624-11G>A ZAP70 mutation in Canadian Mennonites. BMC Med Genet 2016;17:50.
Sherwin JC, Hewitt AW, Ruddle JB, Mackey DA (2008) Genetic isolates in ophthalmic diseases. Ophthalmic Genet 29:149–161.
Strauss KA, Puffenberger EG (2009) Genetics, medicine, and the Plain people. Annu Rev Genomics Hum Genet 10:513–536.
Taşkesen M, Collin GB, Evsikov AV, et al. (2012) Novel Alu retrotransposon insertion leading to Alström syndrome. Hum Genet 131:407–413.
Zlotogora J (1994) High frequencies of human genetic diseases: founder effect with genetic drift or selection? Am J Med Genet 49:10–13.
Information & Authors
Information
Published In
Genetic Testing and Molecular Biomarkers
Volume 21 • Issue Number 6 • June 2017
Pages: 397 - 401
PubMed: 28402684
Copyright
Copyright 2017, Mary Ann Liebert, Inc.
History
Published in print: June 2017
Published online: 1 June 2017
Published ahead of print: 12 April 2017
Topics
Authors
Author Disclosure Statement
No competing financial interests exist.
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Get Access
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.