New Mutation (P575L) in the GUCY2D Gene in an African–American Family with Autosomal Dominant Progressive Cone Degeneration with Incomplete Penetrance

Abstract

Abstract: : Purpose: To characterize the mutation involved in GUCY2D Gene in a Family affected with Autosomal Dominant Progressive Cone Degeneration Methods: We ascertained an African–American family consisting of four generations and affected with cone degeneration. Electroretinograms were performed on some family members. The inheritance pattern of the condition was consistent with autosomal dominant trait. DNA was extracted using the Puregene protocol. Genotyping with micro satellite markers was performed to define the minimal candidate region. Direct manual DNA sequencing was performed on all family members which included19 individuals: 10 clinically unaffected, 9 affected. Multiple sequence alignment was carried out for sequences identified as Guanylate Cyclase in the NCBI database. 244 control chromosomes were tested. Results: A missense mutation P575L was found in exon 8 of the GUCY2D gene on Chromosome 17p13 in 11 members of this family, two of which (14 and 29 years of age) were found to be asymptomatic and clinically unaffected by ophthalmoscopy examination performed at their home. ERG studies were not possible on these two individuals. Affected individuals in this family were heterozygous for this mutation. Conclusions:Genetic analysis of this family identified a previously undescribed mutation P575L in the GUCY2D gene in exon 8. Mutations have been previously reported in exon 13 for the same gene in families with the same phenotype (CORD5 and CORD6). This base pair change, P575L, is unlikely to be a polymorphism because 244 controls did not show this change. This new mutation segregated with the disease in all family members except in two unaffected individuals. This finding suggests that autosomal dominant cone degeneration in this family demonstrated incomplete penetrance much like that found in CORD5. This is the first report known to us of an African –American family affected with autosomal cone degeneration.

Keywords: mutations • retinal degenerations: hereditary • degenerations/dystrophies