Guanylate Cyclase 2D, Membrane

Alternative Names

  • GUCY2D
  • GUC2D
  • Guanylate Cyclase 2D, Retinal
  • GUCY2E, Mouse, Homolog of
  • Rod Outer Segment Membrane Guanylate Cyclase
  • RETGC1
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OMIM Number




Uniprot ID



17,728 bases

No. of Exons


No. of isoforms


Protein Name

Retinal guanylyl cyclase 1

Molecular Mass

120059 Da

Amino Acid Count


Genomic Location


Gene Map Locus


The GUCY2D encodes the membrane bound retinal guanylyl cyclase-1 protein (RetGC-1) which is a member of the membrane guanylyl cyclase family. It is expressed in both cone and rod photoreceptors, but predominantly in the cone outer segments. GUCY2D plays an essential role in normal vision, since it is responsible for a chemical reaction that helps return photoreceptors to their resting state after light exposure. Defects in this protein result in Leber congenital amaurosis 1 and cone-rod dystrophy-6 diseases.

LCA 1 is a severe dystrophy of the retina, presenting typically in the first years of life. The phenotype of LCA patients with mutations in this gene is that of a severe cone-rod dystrophy with photophobia and hyperopia.

Molecular Genetics

The GUCY2D gene is located on chromosome 17p13.1 and covers 17.7 Kb of DNA with 18 coding exons. The protein product consists of 1103 amino acids. Heterozygous mutations in the GUCY2D gene are the cause of autosomal dominantly inherited CD and CRD, whereas homozygous or compound heterozygous mutations cause autosomal recessively inherited Leber congenital amaurosis type 1. At least 50 mutations in the GUCY2D gene have been identified in patients with Leber congenital amaurosis, accounting for 6-21% of all cases of this condition.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000180.4:c.2129C>TJordanNC_000017.11:g.8013118C>TLikely PathogenicLikely PathogenicLeber Congenital Amaurosis 1NG_009092.1:g.15449C>T; NM_000180.4:c.2129C>T; NP_000171.1:p.Ala710Val781725943812327
NM_000180.4:c.2563C>TJordanNC_000017.11:g.8014751C>TPathogenicPathogenicCone-Rod Dystrophy 6NG_009092.1:g.17082C>T; NM_000180.4:c.2563C>T; NP_000171.1:p.Gln855Ter1555635778497765

Other Reports


In all sibs with Leber congenital amaurosis in two consanguineous Arab-Algerian families, Perrault et al. (1996) found homozygosity for a T>C transition in exon 8 at nucleotide 1767 of the GUC2D gene. The nucleotide change converted phenylalanine to serine in the protein. The substitution of an aromatic nonpolar amino acid by an uncharged polar amino acid within the kinase-like domain markedly altered the hydrophobicity of the protein and was expected to affect its stability severely. Perrault et al. (1996) reported the predicted change at amino acid 589 (F589S), but a later study stated that the correct position is 565.

Saudi Arabia

In 37 consanguineous families from Saudi Arabia with Leber congenital amaurosis, Li et al. (2009) performed direct PCR and sequencing for 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, and LCA5). Of 417 individuals from these families, 117 were affected. A homozygous p.R660X mutation in the GUCY2D gene was identified in three affected patients from the same family. In addition, one other family was found to carry benign variations in the GUCY2D gene (c.782T>A and c.248C>T).

Khan et al. (2014) conducted a retrospective case series analysis for a consecutive cohort of Saudi children diagnosed with LCA between 2012 and 2014. A total of 23 patients from 19 consanguineous or endogamous families were screened for mutations in a panel of 14 known LCA genes. Five of these families were found to have mutations in the GUCY2D gene. A novel c.1401dupT (p.Leu468Serfs*89) mutation was identified in two of these families. Another affected family was found to carry a novel c.2285delG (p.Ser762Thrfs*22) mutation. The two other families carried a previously reported homozygous c.1978C>T mutation.

Safieh et al., (2016) described a 6- month old Saudi girl with Leber congenital amaurosis (LCA) born to consanguineous parents.  Direct sequencing for the GUCY2D gene identified a novel (c.743C>T; p.S248L) missense mutation, which was predicted to be pathogenic based on in silico analysis.  The mutation was absent among 300 matched controls.  The authors concluded that this mutation expanded the genotypic spectrum of congenital retinal dystrophies in the Saudi population. 



Perrault et al. (1996) conducted a genetic analysis for three families from Tunisia with Leber congenital amaurosis. The first family was a Jewish Sephardi family in which affected members were homozygous for a 1-bp deletion (c.460delC) in exon 2 at nucleotide 460 of GUC2D that modified the downstream amino acid sequence, abolished an SmaI restriction site, and resulted in a premature translation termination at codon 165. The second family was of Arab Tunisian origin. Affected members were homozygous for a 1-bp deletion in exon 2 at nucleotide 693 (693delC) of GUC2D that modified the downstream amino acid sequence, created a BspMI restriction site, and resulted in a premature translation termination at codon 215. In the third family, a consanguineous Arab Tunisian family, all sibs had homozygosity for a G>T transversion at nucleotide 227 of GUC2D converting an alanine into a serine (p.A52S). Heterozygosity for the same mutation was detected in affected members of a family of Basque ancestry. As the same base change was detected in 2 of 100 controls, it was difficult to decide whether this was a disease-causing mutation or a rare polymorphism.

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