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Search results for: Guanylate Cyclase β1

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#32976546   2020/09/25 To Up

Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases.

Significant number out of 2.2 billion vision impairments in the world can be attributed to genetics. The current study is aimed to decipher the genetic basis of Leber congenital Amaurosis (LCA), Anterior Segment dysgenesis (ASD), and Retinitis Pigmentosa (RP), segregating in four large consanguineous Pakistani families. The exome sequencing followed by segregation analysis via Sanger sequencing revealed the LCA phenotypes segregating in families GCUF01 and GCUF04 can be attributed to c.465G>T (p.(Gln155His)) missense and novel c.139_140delinsA p.(Pro47Trhfster38) frameshift variant of AIPL1 and GUCY2D, respectively. The c.1843A>T (p.(Lys615*) truncating allele of MERTK is homozygous in all the affected individuals, presumably suffering with RP, of the GCUF02 family. Meanwhile, co-segregation of the ASD phenotype and the c.289A>G (p.(Ile97Val)) variant of FOXE3 was found in the GCUF06 family. All the identified variants were either absent or present in very low frequencies in the control databases. Our in-silico analyses and 3D molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MERTK, GUCY2D, and FOXE3 were categorized as "pathogenic" or "likely pathogenic", while the missense variant found in AIPL1 was deemed to have "uncertain significance" based upon the variant pathogenicity guidelines from the American College of Medical Genetics and Genomics (ACMG). This paper highlights the genetic diversity of vision disorders in the Pakistani population and reports the identification of four novel mutations in families who segregate clinically heterogeneous eye diseases. Our results give insight into the genotype-phenotype correlations of AIPL1, FOXE3, MERTK, and GUCY2D variants.
Muhammad Rashid, Muhammad Qasim, Rafaqat Ishaq, Shazia Anwer Bukhari, Zureesha Sajid, Usman Ali Ashfaq, Asma Haque, Zubair M Ahmed

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#32493772   2020/06/03 To Up

Two clusters of surface-exposed amino acid residues enable high-affinity binding of retinal degeneration-3 (RD3) protein to retinal guanylyl cyclase.

Retinal degeneration-3 (RD3) protein protects photoreceptors from degeneration by preventing retinal guanylyl cyclase (RetGC) activation via calcium-sensing guanylyl cyclase-activating proteins (GCAP), and RD3 truncation causes severe congenital blindness in humans and other animals. The three-dimensional structure of RD3 has recently been established, but the molecular mechanisms of its inhibitory binding to RetGC remain unclear. Here, we report the results of probing 133 surface-exposed residues in RD3 by single substitutions and deletions to identify side chains that are critical for the inhibitory binding of RD3 to RetGC. We tested the effects of these substitutions and deletions by reconstituting purified RD3 variants with GCAP1-activated human RetGC1. Although the vast majority of the surface-exposed residues tolerated substitutions without loss of RD3's inhibitory activity, substitutions in two distinct narrow clusters located on the opposite sides of the molecule effectively suppressed RD3 binding to the cyclase. The first surface-exposed cluster included residues adjacent to Leu in the loop connecting helices 1 and 2. The second cluster surrounded Arg on a surface of helix 3. Single substitutions in those two clusters drastically, up to 245-fold, reduced the IC for the cyclase inhibition. Inactivation of the two binding sites completely disabled binding of RD3 to RetGC1 in living HEK293 cells. In contrast, deletion of 49 C-terminal residues did not affect the apparent affinity of RD3 for RetGC. Our findings identify the functional interface on RD3 required for its inhibitory binding to RetGC, a process essential for protecting photoreceptors from degeneration.
Igor V Peshenko, Alexander M Dizhoor

1829 related Products with: Two clusters of surface-exposed amino acid residues enable high-affinity binding of retinal degeneration-3 (RD3) protein to retinal guanylyl cyclase.

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#32255808   2020/04/07 To Up

The pathogenicity of novel GUCY2D mutations in Leber congenital amaurosis 1 assessed by HPLC-MS/MS.

Leber congenital amaurosis (LCA) is a group of severe congenital retinal diseases. Variants in the guanylate cyclase 2D gene (GUCY2D), which encodes guanylate cyclase 1 (ROS-GC1), are associated with LCA1 and account for 6%-21% of all LCA cases. In this study, one family with LCA1 was recruited from China. A combination of next generation sequencing and Sanger sequencing was used to screen for disease-causing mutations. We found three novel mutations (c.139delC, p.Ala49Profs*36; c.835G>A, p.Asp279Asn and c.2783G>A, p.Gly928Glu) in the GUCY2D gene. Proband III-2 carries mutations c.139delC and c.2783G>A, which are inherited from the heterozygous mutation carriers, II-2 (c.139delC) and II-3 (c.2783G>A) that possess c.139delC and c.2783G>A. Additionally, II-8 carries heterozygous mutation c.835G>A. Sanger sequencing was used to confirm the presence of the three novel mutations in other family members. Mutation c.139delC results in a truncated protein. Mutations c.835G>A and c.2783G>A significantly reduce the catalytic activity of ROS-GC1. Our findings highlight the gene variants range of LCA. Moreover, HPLC-coupled tandem mass spectrometry (HPLC-MS/MS) was used to analyze the concentration of 3',5'-cyclic guanosine monophosphate (cGMP), suggesting that HPLC-MS/MS is an effective alternative method to evaluate the catalytic activity of wild-type and mutant ROS-GC1.
Xue Feng, Tianying Wei, Junhui Sun, Yuqin Luo, Yanan Huo, Ping Yu, Jiao Chen, Xiaoming Wei, Ming Qi, Yinghui Ye

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#32173907   2020/03/16 To Up

Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling-induced cone degeneration in cyclic nucleotide-gated channel deficiency.

Photoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca influx in rod and cone photoreceptors. Mutations in cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. Mice lacking functional cone CNG channel show endoplasmic reticulum (ER) stress-associated cone degeneration. The elevated cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) signaling and upregulation of the ER Ca channel ryanodine receptor 2 (RyR2) have been implicated in cone degeneration. This work investigates the potential contribution of RyR2 to cGMP/PKG signaling-induced ER stress and cone degeneration. We demonstrated that the expression and activity of RyR2 were highly regulated by cGMP/PKG signaling. Depletion of cGMP by deleting retinal guanylate cyclase 1 or inhibition of PKG using chemical inhibitors suppressed the upregulation of RyR2 in CNG channel deficiency. Depletion of cGMP or deletion of Ryr2 equivalently inhibited unfolded protein response/ER stress, activation of the CCAAT-enhancer-binding protein homologous protein, and activation of the cyclic adenosine monophosphate response element-binding protein, leading to early-onset cone protection. In addition, treatment with cGMP significantly enhanced Ryr2 expression in cultured photoreceptor-derived Weri-Rb1 cells. Findings from this work demonstrate the regulation of cGMP/PKG signaling on RyR2 in the retina and support the role of RyR2 upregulation in cGMP/PKG signaling-induced ER stress and photoreceptor degeneration.
Fan Yang, Hongwei Ma, Michael R Butler, Xi-Qin Ding

2793 related Products with: Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling-induced cone degeneration in cyclic nucleotide-gated channel deficiency.

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#32165824   2020/02/24 To Up

Copy number variations and multiallelic variants in Korean patients with Leber congenital amaurosis.

We comprehensively evaluated the mutational spectrum of Leber congenital amaurosis (LCA) and investigated the molecular diagnostic rate and genotype-phenotype correlation in a Korean cohort.
Dongheon Surl, Saeam Shin, Seung-Tae Lee, Jong Rak Choi, Junwon Lee, Suk Ho Byeon, Sueng-Han Han, Hyun Taek Lim, Jinu Han

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#32009068   2020/01/31 To Up

Novel GUCY2D Variant (E843Q) at Mutation Hotspot Associated with Macular Dystrophy in a Japanese Patient.

The GUCY2D (guanylate cyclase 2D) gene encodes a photoreceptor guanylate cyclase (GC-E), that is predominantly expressed in the cone outer segments. Mutations in the GUCY2D lead to severe retinal disorders such as autosomal dominant cone-rod dystrophy (adCRD) and autosomal recessive Leber congenital amaurosis type 1. The purpose of this study was to identify the phenotype of a Japanese patient with a probably pathogenic GUCY2D variant.
Yukito Takeda, Daiki Kubota, Noriko Oishi, Kaori Maruyama, Kiyoko Gocho, Kunihiko Yamaki, Tsutomu Igarashi, Hiroshi Takahashi, Shuhei Kameya

1989 related Products with: Novel GUCY2D Variant (E843Q) at Mutation Hotspot Associated with Macular Dystrophy in a Japanese Patient.

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#31882816   2019/12/27 To Up

Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A.

Missense mutations in the GUCA1A gene encoding guanylate cyclase-activating protein 1 (GCAP1) are associated with autosomal dominant cone/cone-rod (CORD) dystrophies. The nature of the inheritance pattern implies that a pool of normal GCAP proteins is present in photoreceptors together with the mutated variant. To assess whether human GCAP1 and GCAP2 may similarly regulate the activity of the retinal membrane guanylate cyclase GC-1 (GC-E) in the presence of the recently discovered E111V-GCAP1 CORD-variant, we combined biochemical and in silico assays. Surprisingly, human GCAP2 does not activate GC1 over the physiological range of Ca whereas wild-type GCAP1 significantly attenuates the dysregulation of GC1 induced by E111V-GCAP1. Simulation of the phototransduction cascade in a well-characterized murine system, where GCAP2 is able to activate the GC1, suggests that both GCAPs can act in a synergic manner to mitigate the effects of the CORD-mutation. We propose the existence of a species-dependent compensatory mechanism. In murine photoreceptors, slight increases of wild-type GCAPs levels may significantly attenuate the increase in intracellular Ca and cGMP induced by E111V-GCAP1 in heterozygous conditions. In humans, however, the excess of wild-type GCAP1 may only partly attenuate the mutant-induced dysregulation of cGMP signaling due to the lack of GC1-regulation by GCAP2.
Daniele Dell'Orco, Giuditta Dal Cortivo

2076 related Products with: Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A.

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#31704230   2019/11/05 To Up

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies.

To describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies.
Zaina Bouzia, Michalis Georgiou, Sarah Hull, Anthony G Robson, Kaoru Fujinami, Tryfon Rotsos, Nikolas Pontikos, Gavin Arno, Andrew R Webster, Alison J Hardcastle, Alessia Fiorentino, Michel Michaelides

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#31470097   2019/08/27 To Up

Possible dual contribution of a novel GUCY2D mutation in the development of retinal degeneration in a consanguineous population.

Molecular characterization of novel mutations in Leber Congenital Amaurosis (LCA) disease improves the disease diagnosis and contributes to the development of preventive and therapeutic approaches. We studied an isolated inbred population in Iran with a high prevalence of retinal degeneration with clinical variability. The clinical examinations were performed on eight patients belonging to three consanguineous families. The identical-by-descent (IBD) mapping technique was employed to identify the shared loci in patients. Subsequently, Sanger sequencing of the GUCY2D gene, in silico analysis, as well as segregation study were conducted. The whole-exome sequencing method was applied for negative cases of GUCY2D mutation, followed by segregation study in suspected variants among families. A novel deletion mutation in the GUCY2D gene can explain the emergence of LCA-1 in most patients but not all. Besides, a heterozygous variant of uncertain significance (VUS) was observed in the BEST1 gene in some healthy and participant patients. These results further support inter/intra-familial clinical heterogeneity in retinal dystrophy and suggest that screening the GUCY2D gene would be needed for the diagnosis of LCA in Iranian people living in the central regions. The variant in the BEST1 gene might be considered a benign heterozygous variant; however, we hypothesized a possible double heterozygosity in both GUCY2D and BEST1 genes that may cause the pathogenesis of cone-rod dystrophy-6 (CRD-6) disease. This would propose a new scenario for the pathogenesis of a monogenic disorder such as CRD-6 disease in which other genetic elements may be involved in the development of the disease.
Ahmad Reza Salehi Chaleshtori, Masoud Garshasbi, Ali Salehi, Mehrdad Noruzinia

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#31428582   2019/08/02 To Up

Gene Expression Profiling Analysis Reveals Putative Phytochemotherapeutic Target for Castration-Resistant Prostate Cancer.

Prostate cancer is the leading cause of cancer death among men globally, with castration development resistant contributing significantly to treatment failure and death. By analyzing the differentially expressed genes between castration-induced regression nadir and castration-resistant regrowth of the prostate, we identified soluble guanylate cyclase 1 subunit alpha as biologically significant to driving castration-resistant prostate cancer. A virtual screening of the modeled protein against 242 experimentally-validated anti-prostate cancer phytochemicals revealed potential drug inhibitors. Although, the identified four non-synonymous somatic point mutations of the human soluble guanylate cyclase 1 gene could alter its form and ligand binding ability, our analysis identified compounds that could effectively inhibit the mutants together with wild-type. Of the identified phytochemicals, (8'R)-neochrome and (8'S)-neochrome derived from the Spinach () showed the highest binding energies against the wild and mutant proteins. Our results identified the neochromes and other phytochemicals as leads in pharmacotherapy and as nutraceuticals in management and prevention of castration-resistance prostate cancers.
Solomon Oladapo Rotimi, Oluwakemi Anuoluwapo Rotimi, Abdulkadir Ayo Salako, Paul Jibrin, Jelili Oyelade, Emeka E J Iweala

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