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GUCY2D
guanylate cyclase 2D, retinal
The GUCY2D gene provides instructions for a protein crucial in vision, particularly in the retina's photoreceptor cells, and is associated with inherited retinal diseases. GUCY2D encodes guanylate cyclase 2D, a protein essential for the phototransduction process in the retina.
GUCY2D is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The GUCY2D gene, also known as guanylate cyclase 2D, plays a critical role in human vision. It provides the blueprint for a protein predominantly found in the specialised tissue at the back of the eye called the retina, specifically within its light-sensing photoreceptor cells. Pathogenic variants in GUCY2D are implicated in various inherited retinal dystrophies, which can lead to significant vision loss.
What the gene does
The GUCY2D protein is integral to the process of phototransduction, which converts light into electrical signals the brain interprets as vision [PMID:16121280]. This protein is located within photoreceptors, which include rods for low-light vision and cones for bright light and colour vision. Following light stimulation, photoreceptors undergo chemical reactions that close ion channels. The GUCY2D protein is involved in the subsequent reaction that re-opens these channels, allowing the photoreceptor cells to reset and be ready for further light stimulation. This resetting mechanism is fundamental for continuous visual perception [PMID:16121280].
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Chromosome location
The GUCY2D gene is situated on chromosome 17, specifically at position 17p13.1. This location indicates its precise address within the human genome. Understanding the gene's chromosomal position is important for genetic mapping and identifying its proximity to other genes.
Protein structure
The GUCY2D protein consists of 1103 amino acids. It features a Protein kinase domain spanning amino acids 525-808. Further along the protein, a Guanylate cyclase domain is found from amino acids 880-1010. Additionally, a Disordered region is identified between amino acids 1065-1103.
Key variants
Variants within the GUCY2D gene can alter the function of the encoded protein, leading to various inherited retinal disorders [PMID:10090883]. These genetic changes can impair the protein's ability to facilitate the phototransduction process, affecting the retina's capacity to properly respond to light. The clinical impact of GUCY2D variants can range from severe vision loss from infancy to later-onset conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
g.8015743del | - | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.-127_1566+2del | - | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.1762C>T | p.Arg588Trp | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.1956+1G>A | - | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.2633_2636del | p.Gln878fs | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.722-1G>T | - | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.726del | p.Ile243fs | Pathogenic | ★★★☆ | GUCY2D-related recessive retinopathy |
c.1753C>T | p.Gln585Ter | Pathogenic | ★★☆☆ | GUCY2D-related disorders |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Leber congenital amaurosis 1 |
c.2291del | p.Pro764fs | Pathogenic/Likely pathogenic | ★★☆☆ | Choroidal dystrophy, central areolar, 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the GUCY2D gene are a recognised cause of several inherited retinal diseases. These include Leber congenital amaurosis type 1, a severe eye disorder typically presenting with significant vision loss in infancy [PMID:10090883]. GUCY2D variants are also associated with cone-rod dystrophy type 6, which generally manifests later in life with progressive central and colour vision loss.
UK clinical status
The GUCY2D gene is included in the UK NHS Genomic Medicine Service's national gene panels. It is part of the "Retinal disorders" panel (R32), which is categorised as 'green', indicating that there is strong evidence for the gene's association with these conditions and that testing is routinely performed.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the GUCY2D gene?
The GUCY2D gene provides instructions for a protein crucial for phototransduction, the process by which light is converted into electrical signals in the eye's photoreceptor cells. It helps these cells reset after light exposure, allowing for continuous vision.
Which conditions are associated with variants in the GUCY2D gene?
Variants in GUCY2D are primarily associated with Leber congenital amaurosis (GUCY2D), a severe retinal disorder causing early-onset vision loss. They can also lead to conditions like cone-rod dystrophy type 6, which typically involves progressive central and colour vision impairment.
How does the GUCY2D protein contribute to vision?
The GUCY2D protein is involved in returning photoreceptor cells to their 'dark' state. After light stimulates these cells and causes ion channels to close, the GUCY2D protein facilitates a reaction that re-opens these channels, preparing the photoreceptors for further light detection.
References
- Boulanger-Scemama E, El Shamieh S, Démontant V. Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation. Orphanet journal of rare diseases. 2015. PMID: 26103963
- Ugur Iseri SA, Durlu YK, Tolun A. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis. European journal of human genetics : EJHG. 2010. PMID: 20517349
- Kitiratschky VB, Wilke R, Renner AB. Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Investigative ophthalmology & visual science. 2008. PMID: 18487367
- Ito S, Nakamura M, Ohnishi Y. Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the GUCY2D gene in Japanese patients. Japanese journal of ophthalmology. 2004. PMID: 15175914
- Hanein S, Perrault I, Olsen P. Evidence of a founder effect for the RETGC1 (GUCY2D) 2943DelG mutation in Leber congenital amaurosis pedigrees of Finnish origin. Human mutation. 2002. PMID: 12325031
- Rozet JM, Perrault I, Gerber S. Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA). Investigative ophthalmology & visual science. 2001. PMID: 11328726
- Payne AM, Morris AG, Downes SM. Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies. Journal of medical genetics. 2001. PMID: 11565546