Analysis of the ARMD1 locus: Evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Francis PJ, Acott TS. Hum Mol Genet 2003;12:3315–3323

Abstract

Identification of the genes involved in age-related macular degeneration (AMD) will lead to a better understanding of the biology of the disease at the molecular level. Previously, this group mapped the ARMD1 gene to 1q25-31 in a large family with AMD. In this study, the ARMD1 locus was narrowed 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, A16263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this very large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gin5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops the 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 Gin5345Arg 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.—Hans E. Grossniklaus