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

Alström syndrome (OMIM 203800) is an autosomal recessive disease, characterized by cone-rod retinal dystrophy, cardiomyopathy and type 2 diabetes mellitus, that has been mapped to chromosome 2p13 (refs 1-5). We have studied an individual with Alström syndrome carrying a familial balanced reciprocal chromosome translocation (46, XY,t(2;11)(p13;q21)mat) involving the previously implicated critical region. We postulated that this individual was a compound heterozygote, carrying one copy of a gene disrupted by the translocation and the other copy disrupted by an intragenic mutation. We mapped the 2p13 breakpoint on the maternal allele to a genomic fragment of 1.7 kb which contains exon 4 and the start of exon 5 of a newly discovered gene (ALMS1); we detected a frameshift mutation in the paternal copy of the gene. The 12.9-kb transcript of ALMS1 encodes a protein of 4,169 amino acids whose function is unknown. The protein contains a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. We have detected six different mutations (two nonsense and four frameshift mutations causing premature stop codons) in seven families, confirming that ALMS1 is the gene underlying Alström syndrome. We believe that ALMS1 is the first human disease gene characterized by autosomal recessive inheritance to be identified as a result of a balanced reciprocal translocation.

Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.

Alström syndrome is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1. Central features of Alström syndrome include obesity, insulin resistance, and type 2 diabetes, and therefore investigating ALMS1 function stands to offer new insights into the pathogenesis of these common conditions. To begin this process, we have analyzed the subcellular localization and tissue distribution of ALMS1 by immunofluorescence. We show that ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. Fibroblasts with disrupted ALMS1 assemble primary cilia and microtubule cytoskeletons that appear normal, suggesting that the Alström syndrome phenotype results from impaired function rather than abnormal development. Coupled with recent data on the complex phenotype of Bardet-Biedl syndrome, our findings imply an unexpected central role for basal body and centrosome dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Unraveling the molecular mechanisms underlying the Alström syndrome phenotype will be important in the search for new therapeutic targets for these conditions.

Narrowing the critical region within 11q24-qter for hypoplastic left heart and identification of a candidate gene, JAM3, expressed during cardiogenesis.

Hypoplastic left heart is a severe human congenital heart defect characterized by left ventricular hypoplasiawith aortic and mitral valve atresia. A genetic etiology is indicated by an association of the hypoplastic left heart phenotype with terminal 11q deletions that span approximately 20 Mb (distal to FRA11B in 11q23). Here we define the breakpoints in four patients with heart defects in association with distal 11q monosomy and refine the critical region to an approximately 9-Mb region distal to D11S1351. Within this critical region we have identified JAM3, a member of the junction adhesion molecule family, as a strong candidate gene for the cardiac phenotype on the basis that it is expressed during human cardiogenesis in the structures principally affected in hypoplastic left heart.