New Mutation, P575L, in the GUCY2D Gene in a Family With Autosomal Dominant Progressive Cone Degeneration

Abstract

To clinically characterize the retinal abnormalities and identify the mutation causing an autosomal dominant cone degeneration in an African American family. Methods: Clinical characterization of family members using fundus photography, fluorescein angiography, and electrophysiological testing. Standard molecular genetic methods were used, including segregation analysis and DNA sequencing of candidate genes. Genetic mutation screening was performed in 20 individuals: 10 clinically unaffected and 10 affected. Results: The affected family members had findings consistent with a primary cone degeneration. A novel mutation, P575L, was found in exon 8 of the GUCY2D gene in 12 members of this family. Conclusions: Inadditiontofindingapreviouslyundescribed mutation in GUCY2D, 2 of the family members who were thought to be unaffected through routine clinical examinations also had this mutation. These findings suggest that autosomal dominant cone degeneration in this family demonstrated age-dependent penetrance, which appears incomplete. This is the first African American family reported with a mutation in GUCY2D. Because the disease in this family and the one we previously described is primarily a cone degeneration, this disease should be more properly classified as cone degeneration and be called cone degeneration 2. Clinical Relevance: This study helps to expand the phenotype of the disease and help clinicians identify patients with cone degenerations.

Dysfunction of outer segment guanylate cyclase caused by retinal disease related mutations

“…In the present work we tested the biochemical consequences of three point mutations ( Figure 1 ). The mutation P575L was found in a family, where clinically affected members suffer from progressive cone degeneration (Small et al, 2008). The amino acid substitution is located in the juxtamembrane domain (JMD), which is a specific region of sensory GCs upstream of the kinase homology domain (KHD).…”

A detailed phenotypic description of autosomal dominant cone dystrophy due to a de novo mutation in the GUCY2D gene

“…7 Two mutation sites in GUCY2D, the codons 575 and 838, have been reported to cause autosomal dominant cone dystrophy or CORD. 5,8 Recently, the mutation p.V933A was described in GUCY2D associated with the phenotype of autosomal dominant central areolar choroidal dystrophy, a condition similar to CORD. 9 The importance of identifying this condition is paramount as, using a gene therapy technique, a partial restoration of visual function has been demonstrated in a GUCY2D knockout mouse model increasing the likelihood of eventual treatment in humans.…”

Gucy2d- Or Guca1a-Related Autosomal Dominant Cone–rod Dystrophy

“…Heterozygous mutations of the GUCY2D and GUCA1A genes have been shown to cause autosomal dominant CD and CRD. [1][2][3][4][5][6][7][8][9] Both genes are expressed in cone and rod photoreceptors and are essential for their functional integrity. [10][11][12] GUCY2D encodes the retinal guanylate cyclase (retGC-1), which is responsible for the cyclic guanosine monophosphate synthesis in the recovery of the dark state after light activation within these cells.…”