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Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

ABSTRACT: Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

SUBMITTER: Wallace S

PROVIDER: S-EPMC4949143 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

Wallace S S Guo D-C DC Regalado E E Mellor-Crummey L L Bamshad M M Nickerson D A DA Dauser R R Hanchard N N Marom R R Martin E E Berka V V Sharina I I Ganesan V V Saunders D D Morris S A SA Milewicz D M DM

Clinical genetics 20160218 4

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals fro ...[more]

PMID: 26777256

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Project description:BackgroundMoyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA.MethodsExome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses.ResultsCausative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia.ConclusionsWe show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.

Project description:Although sex differences in asthma severity are recognized, the mechanisms by which sex steroids such as estrogen influence the airway are still under investigation. Airway tone, a key aspect of asthma, represents a balance between bronchoconstriction and dilation. Nitric oxide (NO) from the bronchial epithelium is an endogenous bronchodilator. We hypothesized that estrogens facilitate bronchodilation by generating NO in bronchial epithelium. In acutely dissociated human bronchial epithelial cells from female patients exposure to 17?-estradiol (E(2); 10 pM-100 nM) resulted in rapid increase of diaminofluorescein fluorescence (NO indicator) within minutes, comparable with that induced by ATP (20 ?M). Estrogen receptor (ER) isoform-specific agonists (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) (ER?) and diaryl-propionitrile (DPN) (ER?) stimulated NO production to comparable levels and at comparable rates, whereas the ER antagonist 7?,17?-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780) (1 ?M) was inhibitory. Estrogen effects on NO were mediated via caveolin-1 (blocked using the caveolin-1 scaffolding domain peptide) and by increased intracellular calcium concentration [prevented by 20 ?M 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester but not by blocking Ca(2+) influx using LaCl(3)]. Estrogen increased endothelial NO synthase activation (inhibited by 100 ?M N(G)-nitro-l-arginine methyl ester) and phosphorylated Akt. In epithelium-intact human bronchial rings contracted with acetylcholine (1 ?M), E(2), THC, and DPN all produced acute bronchodilation in a dose-dependent fashion. Such bronchodilatory effects were substantially reduced by epithelial denudation. Overall, these data indicate that estrogens, acting via ER? or ER?, can acutely produce NO in airway epithelium (akin to vascular endothelium). Estrogen-induced NO and its impairment may contribute to altered bronchodilation in women with asthma.

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Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

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Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

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