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D. W. Schultz, C. J. Runckel, J. Duan, M. Schain, R. G. Weleber, P. J. Francis, T. S. Acott, M. L. Klein; A Novel Mutation in the Complement Factor H Gene in a Family With Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4626.
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To identify the variation associated with age-related macular degeneration (AMD) in a family with 7 affected members.
The Complement Factor H (CFH) and Factor H Related-5 (FHR-5) genes were screened for mutations through sequencing on an Applied Biosystems 3130XL genetic analyzer.
A family was collected and ascertained with seven members diagnosed with AMD, five of whom were under 60 years of age. Using an AMD model that accounts for age-dependent penetrance and the presence of phenocopies, this family yielded a parametric HLOD score on chromosome 1 of 2.3 at D1S1660, approximately 2 Mb from the CFH gene. In contrast, the second most significant locus for this family with this model had an HLOD of less than 1.2. Mutational screening identified a G1081A (NM_000186) change in exon 8 of CFH in all affected members of this family. This alteration predicts a cysteine to tyrosine change at amino acid 325 in the protein sequence of CFH. The CFH gene consists of 20 short consensus repeats (SCRs). This cysteine is part of one of the two disulfide bonds that are conserved in all SCRs. Ault et al have previously shown in a compound heterozygote that a C518R change in SCR9 and a C991R change in SCR16 of CFH result in retention of the 155 kDa CFH protein in the endoplasmic reticulum.
A novel mutation in the CFH gene has been identified in an AMD family with 7 affected members. Although the family is not large enough on its own to produce a significant LOD score, given the association of CFH with AMD, the mutation appears likely to be involved in AMD.
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