GUCY2D – Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophy, presenting in infancy with profound vision loss, nystagmus, and extinguished electroretinogram (ERG). The photoreceptor guanylate cyclase gene GUCY2D (HGNC:4689) encodes retinal guanylate cyclase 1 (RetGC1), a key enzyme in phototransduction. Biallelic pathogenic variants in GUCY2D underlie LCA type 1 (LCA1), accounting for 6–21% of cases (PMID:8944027).

Genetic Evidence

GUCY2D‐related LCA follows an autosomal recessive inheritance pattern. Across multiple cohorts, at least 23 unrelated probands harbor biallelic GUCY2D variants, including homozygous and compound heterozygous changes in 15 families (PMID:11035546; PMID:27475985). Segregation analysis in a large Bedouin kindred demonstrated cosegregation of a novel missense variant c.2129C>T (p.Ala710Val) with disease in eight affected relatives (PMID:27475985). Case reports further document compound heterozygous splice site (c.2113+2_2113+3insT) and missense (c.2302C>T (p.Arg768Trp)) mutations in Japanese twins with classic LCA features (PMID:26097748).

Variant Spectrum and Phenotype

To date, over 100 GUCY2D variants have been reported in LCA1, including missense (e.g., c.2302C>T (p.Arg768Trp)), nonsense, frameshift, and splicing mutations. The c.2302C>T (p.Arg768Trp) variant is recurrent in diverse populations, supporting its pathogenicity. Phenotypically, affected individuals exhibit early-onset severe visual impairment, nystagmus (HP:0000639), photophobia (HP:0000613), and high hypermetropia (HP:0000540), with fundus examination showing preserved photoreceptors in the macula despite functional loss (PMID:12623820).

Functional Evidence

Biochemical assays of RetGC1 mutant proteins reveal complete loss of cGMP synthesis for catalytic‐domain mutants and aberrant regulation by Ca2+‐sensor GCAPs for dimerization‐domain variants (PMID:11328726; PMID:11115851). Knockout and double‐knockout mouse models lacking RetGC1 demonstrate absence of cone ERG responses and progressive photoreceptor degeneration, both rescued by AAV‐mediated expression of wild‐type GUCY2D, confirming RetGC1’s essential role and therapeutic targetability (PMID:20593011).

Integration and Conclusion

The accumulation of genetic and functional data establishes a Strong gene–disease association for GUCY2D and LCA1. Genetic evidence includes ≥23 probands across 15 families with segregation and concordant clinical findings. Functional studies demonstrate loss‐of‐function or misregulation of RetGC1 consistent with photoreceptor pathology. These data support ongoing and future gene‐augmentation trials targeting GUCY2D in LCA1. Key take‐home: early genetic diagnosis of GUCY2D‐associated LCA enables prognostic counseling and enrollment in emerging gene therapies.

References

• Nature Genetics • 1996 • Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. PMID:8944027
• Ophthalmic Genetics • 2000 • Mutational analysis and clinical correlation in Leber congenital amaurosis. PMID:11035546
• Ophthalmology • 2003 • Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis. PMID:12623820
• BMC Medical Genetics • 2016 • Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. PMID:27475985
• Journal of Ophthalmology • 2015 • Novel GUCY2D Gene Mutations in Japanese Male Twins with Leber Congenital Amaurosis. PMID:26097748
• Investigative Ophthalmology & Visual Science • 2001 • Complete abolition of the retinal-specific guanylyl cyclase catalytic ability consistently leads to Leber congenital amaurosis. PMID:11328726
• Human Molecular Genetics • 2000 • Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity. PMID:11115851
• PLoS One • 2010 • Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 knockout mouse. PMID:20593011

Evidence Based Scoring (AI generated)