Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Invest 2008 May 16. [Epub ahead of print]
AbstractPURPOSE. Heterozygous mutations in the GUCY2D gene, which
encodes the membrane-bound retinal guanylyl cyclase-1 protein
(RetGC-1), have been shown to cause autosomal dominant
inherited cone degeneration and cone–rod degeneration
(adCD, adCRD). The present study was a comprehensive
screening of the GUCY2D gene in 27 adCD and adCRD unrelated
families of these rare disorders.
METHODS. Mutation analysis was performed by direct sequencing
as well as PCR and subsequent restriction length polymorphism
analysis (PCR/RFLP). Haplotype analysis was performed
in selected patients by using microsatellite markers.
RESULTS. GUCY2D gene mutations were identified in 11 (40%)
of 27 patients, and all mutations clustered to codon 838,
including two known and one novel missense mutation:
p.R838C, p.R838H, and p.R838G. Haplotype analysis showed
that among the studied patients only two of the six analyzed
p.R838C mutation carriers shared a common haplotype and
that none of the p.R838H mutation carriers did.
CONCLUSIONS. GUCY2D is a major gene responsible for progressive
autosomal dominant cone degeneration. All identified mutations
localize to codon 838. Haplotype analysis indicates that
in most cases these mutations arise independently. Thus,
codon 838 is likely to be a mutation hotspot in the GUCY2D