Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family.
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.
Schultz
Dennis W
DW
Macular Degeneration Center, Casey Eye Institute, Portland, OR 97239-4197, USA. schultzd@ohsu.edu
Klein
Michael L
ML
Humpert
Andrea J
AJ
Luzier
Christina W
CW
Persun
Vesna
V
Schain
Mitchell
M
Mahan
Alison
A
Runckel
Charles
C
Cassera
Maria
M
Vittal
Vasavi
V
Doyle
Trudy M
TM
Martin
Tammy M
TM
Weleber
Richard G
RG
Francis
Peter J
PJ
Acott
Ted S
TS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015415:Biomarkers; D002460:Cell Line; D017124:Conserved Sequence; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007136:Immunoglobulins; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping
D015415:Biomarkers; D016326:Extracellular Matrix Proteins; C488168:HMCN1 protein, human; D007136:Immunoglobulins