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

Abstract

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.Alström syndrome was initially mapped to an interval of 6.1 cM between loci D2S286 and D2S327 (refs 3-5). Although several candidate genes have been investigated, no mutations have previously been identified [6][7][8] . We have shown that the 2p13 breakpoint in the individual with the 46,XY,t(2;11)(p13;q21)mat translocation is between these loci by metaphase fluorescence in situ hybridization (FISH) analysis using the BACs RP11-355F16 (containing D2S286) and RP11-480F1 (located 150 kb proximal to D2S327) as probes. The BAC RP11-582H21 crosses the translocation breakpoint (Fig. 1a,b) and is overlapped by RP11-79N18, which contains CCT7, a member of a chaperonin gene

Positional Identification of Hypertension Susceptibility Genes on Chromosome 2

“…27 ALMS1 is a gene recently implicated in Alstrom syndrome, a rare Mendelian disorder with characteristics including obesity, diabetes, and cardiomyopathy. 28,29 SLC9A2, an Na ϩ /H ϩ exchanger, is expressed in many tissues, including the kidney. 30 SLC20A1 is a sodium-dependent phosphate symporter with expression across tissues, including the kidney.…”

Lack of association between gene variants in the ALMS1 gene and Type 2 diabetes mellitus

“…Autoantibodies are of particular interest in genetically homogenous populations as in Finland [2] and Sardinia [3] since they could provide epidemiological and mechanistic insights into the role of these antibodies in the pathogenesis of diabetes. Such a genetically unique population also exists in the United States.…”

Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome

“…[3][4][5] In addition, mutations in BBS patients have also been identified in MKS1 and CEP290, genes known to cause other ciliopathic phenotypes such as Meckel syndrome and nephronophthisis. 6 Owing to the large number of BBS genes, direct sequencing of all coding exons of these (135 exons for BBS1-12 and 23 exons for ALMS1) is not practical or cost-effective.…”