title: 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.
authors.affiliation: Division of Human Genetics, Southampton University, The Duthie Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Hearn
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Renforth
authors.forename: Cosma
authors.initials: C
authors.lastname: Spalluto
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: Karen
authors.initials: K
authors.lastname: Piper
authors.forename: Sarah
authors.initials: S
authors.lastname: Brickwood
authors.forename: Chris
authors.initials: C
authors.lastname: White
authors.forename: Vincent
authors.initials: V
authors.lastname: Connolly
authors.forename: James F N
authors.initials: JF
authors.lastname: Taylor
authors.forename: Isabelle
authors.initials: I
authors.lastname: Russell-Eggitt
authors.forename: Dominque
authors.initials: D
authors.lastname: Bonneau
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012162:Retinal Degeneration / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D020080:Tandem Repeat Sequences; D014178:Translocation, Genetic