Mutation of ALMS1, a large gene with a tandem repeat of 47 amino acids, causes Alström syndrome.

T Hearn1, GL Renforth1, C Spalluto1, NA Hanley1, K Piper1, S Brickwood1, C White2, V Connolly3, JFN Taylor4, I Russell-Eggitt4, D Bonneau5, M Walker2, DI Wilson1

1Division of Human Genetics, Southampton University, UK. 2Department of Diabetes and Metabolism, University of Newcastle, UK. 3South Cleveland Hospital, Middlesbrough, UK. 4Hospital for Sick Children London UK. 5Department of Medical Genetics, CHU, Angers, France

Alström syndrome (OMIM 203800) is an autosomal recessive disease characterised by cone-rod retinal dystrophy, cardiomyopathy and type II diabetes mellitus that has been mapped to chromosome 2p13 (ref. 1-5). We have investigated an individual with Alström syndrome carrying a familial balanced reciprocal chromosome translocation within the critical region [46, XY,t(2;11)(p13;q21)mat]. We postulated that this individual was a compound heterozygote with one copy of a gene disrupted by the translocation and the other copy by an intragenic mutation. We have mapped the 2p13 breakpoint on the maternal allele to a 1.7 kb genomic fragment containing exon 4 and the start of exon 5 of a novel gene (ALMS1) and detected a frameshift mutation in the paternal copy of the gene. The 12.9 kb ALMS1transcript encodes a 4,169 amino acid protein of unknown function, which contains a large tandem repeat domain comprising 34 imperfect repetitions of a novel 47 amino acid sequence. We have detected six different mutations (2 nonsense and 4 frameshift mutations causing premature STOP codons) in 7 families, confirming ALMS1as the gene responsible for Alström syndrome. We believe ALMS1is the first human disease gene characterized by autosomal recessive inheritance to be identified as a result of a balanced reciprocal translocation.