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.
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References
Russell-Eggitt, I.M. et al. Alström syndrome. Report of 22 cases and literature review. Ophthalmology 105, 1274–1280 (1998).
Marshall, J.D. et al. Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families. Am. J. Med. Genet. 73, 150–161 (1997).
Collin, G.B., Marshall, J.D., Cardon, L.R. & Nishina, P.M. Homozygosity mapping at Alström syndrome to chromosome 2p. Hum. Mol. Genet. 6, 213–219 (1997).
Macari, F. et al. Refinement of genetic localization of the Alström syndrome on chromosome 2p12-13 by linkage analysis in a North African family. Hum. Genet. 103, 658–661 (1998).
Collin, G.B. et al. Alström syndrome: further evidence for linkage to human chromosome 2p13. Hum. Genet. 105, 474–479 (1999).
Collin, G.B., Nishina, P.M., Marshall, J.D. & Naggert, J.K. Human DCTN1: genomic structure and evaluation as a candidate for Alström syndrome. Genomics 53, 359–364 (1998).
Collin, G.B., Marshall, J.D., Naggert, J.K. & Nishina P.M. TGFA: exon-intron structure and evaluation as a candidate gene for Alström syndrome. Clin. Genet. 55, 61–62 (1999).
Chen, F. et al. Characterization of the murine Lbx2 promoter, identification of the human homologue, and evaluation as a candidate for Alström syndrome. Genomics 74, 219–227 (2001).
Leroux, M.R. & Hartl, F.U. Protein folding: versatility of the cytosolic chaperonin TRiC/CCT. Curr. Biol. 10, R260–264 (2000).
Katsanis, N. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nature Genet. 26, 67–70 (2000).
Slavotinek, A. et al. Mutations in MKKS cause Bardet-Biedl syndrome. Nature Genet. 26, 15–16 (2000).
Nagase, T. et al. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4, 141–150 (1997).
Ozaki, K., Fujiwara, T., Nakamura, Y. & Takahashi, E. Isolation and mapping of a novel human kidney- and liver-specific gene homologous to the bacterial acetyltransferases. J. Hum. Genet. 43, 255–258 (1998).
Collin, G.B. et al. Identification of a novel gene causing obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nature Genet. 31 (2002); advance online publication, (DOI: 10.1038/ng867).
Moniaux, N., Escande, F., Porchet, N., Aubert, P. & Batra, S.K. Structural organization and classification of the human mucin genes. Front. Biosci. 6, 1192–1206 (2001).
Matz, M. et al. Amplification of cDNA ends based on template-switching effect and step-out PCR. Nucleic Acids Res. 27, 1558–1560 (1999).
Acknowledgements
We are grateful to M. Rocchi for the PAC 1011O17 and chromosome 11 alphoid FISH probes. We wish to thank D. Wellesley, D. Schapira, A. Moore, S. O'Rahilly, I. Ellis and N. Roper for help ascertaining families. We are very grateful for the help of families and individuals with Alström syndrome and the support of the Juvenile Diabetes Research Foundation (to K.P. and S.B.). N.A.H. is a Department of Health (UK) Clinician Scientist. This study was funded by Diabetes UK.
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Southampton University and the University of Newscastle have submitted a patent application for ALMS1.
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Hearn, T., Renforth, G., Spalluto, C. et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet 31, 79–83 (2002). https://doi.org/10.1038/ng874
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DOI: https://doi.org/10.1038/ng874
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