GUCY2D – Cone-Rod Dystrophy

GUCY2D encodes retinal guanylate cyclase-1 (RetGC-1), and heterozygous missense mutations in this gene are a well-established cause of autosomal dominant cone-rod dystrophy (CORD) ([PMID:18487367]). A single family with autosomal recessive CORD due to a homozygous missense variant c.2846T>C (p.Ile949Thr) illustrates that GUCY2D can underlie both dominant and recessive inheritance modes for CORD ([PMID:20517349]).

Genetic evidence includes the identification of heterozygous codon 838 substitutions—c.2512C>T (p.Arg838Cys), c.2512C>G (p.Arg838Gly), and c.2513G>A (p.Arg838His)—in 11 of 27 unrelated CORD families, clustering at a mutational hotspot and segregating with disease across multiple generations ([PMID:18487367]). Recurrent founder‐independent events at Arg838 account for ~40% of autosomal dominant CORD cases, and a separate homozygous variant in a consanguineous pedigree supports a recessive mechanism ([PMID:20517349]).

Segregation analysis across extended pedigrees demonstrated co-segregation of Arg838 variants in at least 19 affected relatives over four multigenerational families, with no non-penetrant carriers observed ([PMID:18487367]). Functional evidence from in vitro biochemical assays shows that the p.Arg838Cys substitution increases RetGC-1 affinity for GCAP-1, shifts Ca²⁺ sensitivity to higher ranges, and results in constitutive cyclase activation, consistent with a dominant gain-of-function mechanism ([PMID:11115851]; [PMID:10430891]).

Integration of genetic and experimental data indicates that dominant CORD-associated GUCY2D variants act via altered Ca²⁺-dependent regulation of cGMP synthesis, whereas recessive alleles lead to loss of cyclase function. Clinically, GUCY2D testing should include exon 13 hotspot screening for codon 838 substitutions and consideration of rare recessive alleles in patients with CORD.

Key Take-home: GUCY2D variants, particularly codon 838 missense changes, are a frequent and actionable cause of autosomal dominant cone-rod dystrophy, supporting targeted genetic testing and informing prognosis.

References

• European Journal of Human Genetics • 2010 • A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis PMID:20517349
• Investigative Ophthalmology & Visual Science • 2008 • Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration PMID:18487367
• Human Molecular Genetics • 2000 • Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy PMID:11115851
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • Biochemical analysis of a dimerization domain mutation in RetGC-1 associated with dominant cone-rod dystrophy PMID:10430891

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