Disease relevance of GUCY2D

• Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease and is the most severe inherited retinopathy with the earliest age of onset [1].
• PURPOSE: To study the retinal degeneration in an 11 -year-old patient with Leber congenital amaurosis (LCA) caused by mutation in GUCY2D [2].
• PURPOSE: A two-generation consanguineous Pakistani family with autosomal recessive Leber congenital amaurosis (LCA, MIM 204,000) and keratoconus was identified [3].
• Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies [4].
• Two lung cancer antigens were defined: LCA-1, which shared antigenic determinants with GI tumors and fetal lung tissues, and LCA-2, which showed cross-reactivity only with GI tumors [5].

Psychiatry related information on GUCY2D

• The diffusion model () and the leaky competing accumulator model (LCA, ) were tested against two-choice data collected from the same subjects with the standard response time procedure and the response signal procedure [6].
• Case studies demonstrate that the new tool is well suited to support and complement existing methods for decision making in waste and resource management such as LCA [7].
• We have, therefore, examined six brains from cases of sporadic CJD by immunohistochemical labelling of grey and white matter microglia from frontal, parietal, temporal, and occipital lobes, striatum, thalamus, cerebellum and brain stem with RCA-1, LCA, CD68, HLA-DR, and HAM56 [8].

High impact information on GUCY2D

• AIPL1 mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage [1].
• Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally [4].
• The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA [4].
• Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion [9].
• Our results suggest that retGC may synthesize cGMP required for recovery of the dark state after phototransduction [10].

Chemical compound and disease context of GUCY2D

• OBJECTIVES: The aim of this study was to compare the effect of a combination of lansoprazole, clarithromycin, and amoxicillin (LCA) versus placebo on the severity of symptoms in functional dyspepsia patients who were positive for Helicobacter pylori (H. pylori) [11].
• Mutations in the gene coding for photoreceptor specific guanylate cyclase type 1, ROS-GC1, were found to be the cause for the type 1 Leber's congenital amaurosis (LCAI) and cone-rod dystrophy type 6 (CORD6) [12].
• Twenty-seven JXG, ten dermatofibromas (DF), and ten age-matched normal skin specimens were stained using standard immunohistochemistry methods, and all JXGs were fascin+ and CD68+, although 26 of 27 were reactive for HLA-DR, 25 of 27 for Factor XIIIa, 25 of 27 for LCA, 21of 27 for CD4, and 8 of 27 for polyclonal s100 [13].
• Changes in the cell surface glycoproteins were investigated in endometrial adenocarcinomas using eight biotin-labelled lectins (Con A, LCA, WGA, e-PHA, l-PHA, SBA, PNA, LTA) which select for the major classes of N-linked and O-linked oligosaccharides [14].
• In this study, we assessed bone marrow clot and/or core biopsy sections of 19 cases of acute lymphoblastic leukemia (ALL) using routinely decalcified, B5- or formalin-fixed, paraffin-embedded sections and a panel of monoclonal antibodies, including LN1, LN2, L26, Leu-22, UCHL-1, and LCA [15].

Biological context of GUCY2D

• 1. The association of the candidate gene GUCY2D (17p13.1) with the disease phenotype was excluded as no disease-associated mutation was found in any of its exons [16].
• Functional analyses of mutant recessive GUCY2D alleles identified in Leber congenital amaurosis patients: protein domain comparisons and dominant negative effects [17].
• RESULTS: In haplotype analysis, no linkage to LCA5 or GUCY2D loci was detected [18].
• A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber Congenital Amaurosis [19].
• Until recently, the management of patients with LCA relied mainly on clinical examination, electrophysiology, and other ancillary tests [20].

Anatomical context of GUCY2D

• It appears that the heterozygous GUCY2D mutation further disrupts the already compromised photoreceptor function resulting in more severe retinal dysfunction in the older sibling [19].
• CONCLUSIONS: An 11-year-old subject with LCA caused by mutant GUCY2D had only light perception but retained substantial numbers of cones and rods in the macula and far periphery [2].
• This correlates well with the known retinal expression pattern of GUCY2D, which is considerably higher in cone compared with rod photoreceptor cells [21].
• Among the bone marrow samples provided by the 32 limited disease patients, LCA positive cells were detected in 9 (28%) compared to 14 out of the 27 (52%) samples from extensive disease patients (p less than 0.05) [22].
• In situ hybridization analysis of a variety of rhesus monkey tissues showed retGC transcripts to be localized exclusively along the retinal outer nuclear layer, corresponding to the nuclei of the rod and cone photoreceptor cells [10].

Associations of GUCY2D with chemical compounds

• PURPOSE: All mutations in the retinal guanylate cyclase gene (GUCY2D) that causes autosomal dominant cone-rod dystrophy (CORD) are associated with an amino acid substitution in codon 838 [23].
• For the first time, the findings define the linkage of distinct molecular forms of LCA to ROS-GC1 in precise biochemical terms; they also explain the reasons for the insufficient production of cyclic GMP in photoreceptors to sustain phototransduction, which ultimately leads to the degeneration of the photoreceptors [24].
• At nanomolar concentrations of Ca(2+), ROS-GC1 is activated by Ca(2+)-binding proteins named guanylate cyclase activating proteins (GCAPs) [25].
• In addition to GCAPs several other proteins including aktin, tubulin, a glutamic-acid-rich protein and a GTPase accelerating protein (RGS9) were found to interact with ROS-GC1 and probably form a multiprotein complex [26].
• The present studies were undertaken to examine the effectiveness of anti-SCLC rat monoclonal antibodies LCA1 and LC66 plus human complement combined with a derivative of cyclophosphamide (Asta-Z 7557) for the elimination of cancerous clonogenic cells from the graft [27].

Physical interactions of GUCY2D

• A permanent ROS-GC1/GCAP-1 complex is physiologically significant, since it allows a very short response time of cyclase activity when the intracellular Ca2+-concentration changes [28].

Regulatory relationships of GUCY2D

• Recombinant Fugu GCAP1 failed to activate human retinal guanylate cyclase (retGC) in vitro although CD spectroscopy shows that the protein is folded with a similar secondary structure to that of human GCAP1 [29].

Other interactions of GUCY2D

• Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%) [30].
• We suggest that the unusual phenotypic variability in these two siblings with LCA is caused by the modifying effect of a heterozygous GUCY2D mutation observed against the disease background of a homozygous RPE65 mutation [19].
• A reduced dark-adapted isolated rod ERG response and/or maximal combined cone and rod response was recorded in carriers with mutations in the AIPL1, GUCY2D, and RPGRIP1 genes [31].
• The clinical presentation was variable; however, the visual evolution in patients with mutations in GUCY2D and CRX remained stable, while individuals with mutations in the RPE65 gene showed progressive visual loss [32].
• The new GUCY2D mutation (c.3283delC, p.Pro1069ArgfsX37) is the first pathological sequence change reported in the intracellular C-terminal domain of GUCY2D, and did not lead to the commonly associated LCA, but to a juvenile retinitis pigmentosa phenotype [33].

Analytical, diagnostic and therapeutic context of GUCY2D

• The retinal guanylate cyclase (RETGC-1, GDB symbol GUC2D) and pigment epithelium-derived factor (PEDF) genes were analyzed by heteroduplex analysis and direct sequencing for mutations in diseased individuals [3].
• PCR analysis of human-rodent somatic cell hybrids was used to map the GUC2D locus to chromosome 17 [34].
• Direct interaction of retGC with RGS9-1 and its N-terminus is also proved by immunoprecipitation and an overlay technique [35].
• The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans [36].
• Lentiviral vectors containing a retinal pigment epithelium specific promoter for leber congenital amaurosis gene therapy. Lentiviral gene therapy for LCA [37].

References