Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family

Hum Mol Genet. 2003 Dec 15;12(24):3315-23. doi: 10.1093/hmg/ddg348. Epub 2003 Oct 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Biomarkers
  • Cell Line
  • Conserved Sequence
  • Exons
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Haplotypes
  • Humans
  • Immunoglobulins
  • Macular Degeneration / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Physical Chromosome Mapping


  • Biomarkers
  • Extracellular Matrix Proteins
  • HMCN1 protein, human
  • Immunoglobulins