GUCY2D – Cone–Rod Dystrophy 6

GUCY2D (Guanylate Cyclase 2D; HGNC:4689) encodes retinal guanylate cyclase-1 (RetGC-1), a key enzyme in phototransduction. Heterozygous missense mutations at codon 838 cause autosomal dominant cone–rod dystrophy 6 (CORD6; MONDO:0011143), marked by early cone dysfunction and progressive visual loss.

A 13-year-old girl presenting with progressive visual loss and cone dysfunction on electroretinography was found to carry a heterozygous Arg838His substitution in GUCY2D (PMID:21218126). Subsequent analysis of two unrelated American families with CORD5/6 revealed R838C and R838H substitutions segregating with disease, including one mildly affected relative demonstrating incomplete penetrance (PMID:12552567).

Inheritance is autosomal dominant. Codon 838 constitutes a recurrent mutational hotspot yielding R838C, R838H, R838G and R838S variants. At least three unrelated probands have been reported, with one additional affected relative segregating across families.

Biochemical assays of R838C and R838H mutants show constitutive activation of RetGC-1: elevated basal cyclase activity, increased GCAP-1 affinity, and failure to inactivate at high Ca²⁺, consistent with gain-of-function pathology driving photoreceptor degeneration (PMID:12552567).

A transgenic zebrafish model expressing the E837D R838S RetGC-1 mutant recapitulates CORD6 pathology, exhibiting aberrant cone morphology, reduced cone density and thinning of the outer nuclear layer, validating in vivo pathogenicity (PMID:23328348).

Moderate genetic evidence and strong functional concordance support a Moderate ClinGen classification for GUCY2D–CORD6. Targeted sequencing of exon 13 in GUCY2D is recommended for molecular diagnosis, genetic counseling, and selection of patients for future therapeutic interventions.

References

• Retinal cases & brief reports • 2011 • Use of spectral domain-optical coherence tomography to visualize photoreceptor abnormalities in cone-rod dystrophy 6. PMID:21218126
• Human mutation • 2003 • Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance. PMID:12552567
• Experimental eye research • 2013 • Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology. PMID:23328348

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