Overview
Gene (OMIM no.) |
|
Function of gene/protein |
|
Clinical phenotype (OMIM phenotype no.) |
|
Inheritance |
|
Signs for LCA |
|
Signs for AD cone/cone-rod dystrophy |
|
Signs for AR cone-rod dystrophy |
|
Signs for CSNB |
|
Visual function | LCA:
|
Systemic features |
|
Key investigations |
|
Molecular diagnosis | Next generation sequencing
|
Management | |
Therapies under research |
|
Further information |
Additional information
The vast majority of GUCY2D variants are associated with AR-LCA, accounting for 10-20% of total cases.[2] It is also a major cause of AD cone/cone-rod dystrophies (35% of AD cases), with 13 mutations reported and mostly clustered at codon 838 in exon 13, a known mutation hotspot for this phenotype.[1,6] Other less common phenotypes associated with pathogenic GUCY2D mutations that have been reported are:
- AR cone-rod dystrophy (6 affected members in a consanguineous Turkish family)[10]
- AR-CSNB (5 patients from 4 unrelated families)[11]
Genotype-phenotype correlations have been observed in LCA and AD cone/cone-rod dystrophy depending on the resultant activities of GC-E and GCAPs. Both proteins are crucial to photoreceptor recovery after phototransduction. GC-E synthesises cGMP which is converted to GTP upon light activation. The activity of GC-E is regulated by GCAPs (encoded by GUCA1A and GUCA1B), which are activated by low intracellular calcium concentration after photoreceptor hyperpolarisation (phototransduction).[1]
The LCA phenotype is associated with biallelic null mutations, where there is severely reduced or absent GC-E activity. On the other hand, AD cone/cone-rod dystrophy mutations (all missense variants) are functional, but GCAP activation is distorted due to a shift in calcium sensitivity which results in excessive cGMP production. This in turn leads to a persistent influx of calcium ions (depolarisation) into the photoreceptors. The increased calcium ion concentration triggers progressive photoreceptor degeneration.[1]
References
- Sharon D, Wimberg H, Kinarty Y, Koch KW. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D. Prog Retin Eye Res. 2018;63:69-91
- Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions [published correction appears in Br J Ophthalmol. 2019 Jun;103(6):862]. Br J Ophthalmol. 2017;101(9):1147-1154
- Bouzia Z, Georgiou M, Hull S, et al. GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. Am J Ophthalmol. 2020;210:59-70
- Jacobson SG, Cideciyan AV, Sumaroka A, et al. Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations. Am J Ophthalmol. 2017;177:44-57
- Jacobson SG, Cideciyan AV, Peshenko IV, et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013;22(1):168-183
- Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M. Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy [published online ahead of print, 2019 Jan 24]. Br J Ophthalmol. 2019;103(5):711-720
- Lazar CH, Mutsuddi M, Kimchi A, et al. Whole exome sequencing reveals GUCY2D as a major gene associated with cone and cone-rod dystrophy in Israel. Invest Ophthalmol Vis Sci. 2014;56(1):420-430
- Jiang F, Xu K, Zhang X, Xie Y, Bai F, Li Y. GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies. Doc Ophthalmol. 2015;131(2):105-114
- Kelsell RE, Evans K, Gregory CY, Moore AT, Bird AC, Hunt DM. Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p. Hum Mol Genet. 1997;6(4):597-600
- Ugur Iseri SA, Durlu YK, Tolun A. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber’s congenital amaurosis. Eur J Hum Genet. 2010;18(10):1121-1126
- Stunkel ML, Brodie SE, Cideciyan AV, et al. Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D. Am J Ophthalmol. 2018;190:58-68