Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3315-3323
DOI: 10.1093/hmg/ddg348
© 2003 Oxford University Press
Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family
1Macular Degeneration Center, Casey Eye Institute, 2Department of Ophthalmology, Casey Eye Institute, 3Department of Molecular Microbiology and Immunology, 4Department of Molecular and Medical Genetics, and 5Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA
Received July 31, 2003; Accepted October 9, 2003
Age-related macular degeneration (AMD) is a common cause of severe vision loss. Identification of the genes involved in AMD will lead to a better understanding of this disease at the molecular level, which will eventually lead to early detection, prevention and treatment. Previously, we mapped the ARMD1 gene to 1q25–31 in a large family with AMD. Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes. Twenty candidate genes within this region were screened for mutations. Only one DNA variation, an A16,263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gln5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family. The affected status of all but one of those individuals conforms to the age-dependent penetrance observed in AMD. The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed. RT–PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types. Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene.
* To whom correspondence should be addressed at: Casey Eye Institute, CERES, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197, USA. Tel: +1 5034945672; Fax: +1 5034946875; Email: schultzd{at}ohsu.edu
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