A Nonsense ALMS1 Mutation Underlies Alstrom Syndrome in an Extended Mennonite Kindred Settled in North Mexico

摘要

Aim: Alstrom 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.