Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg348
© 2003 by Oxford University Press
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1 From the Macular Degeneration Center, Casey Eye Institute, CERES, Oregon Health & Science University, 3375 SW Terwilliger Blvd., Portland, OR 97239-4197, USA
* To whom correspondence should be addressed. E-mail: schultzd{at}ohsu.edu.
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 14.9Mb 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 8 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 supports the conclusion that HEMICENTIN-1 is the ARMD1 gene.
Article
Analysis of the ARMD1 locus: Evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family
2 From the Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA
3 Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA
4 Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239, USA
5 Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
6 Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA
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