{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:06:57Z","timestamp":1791295617559,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,2,18]],"date-time":"2016-02-18T00:00:00Z","timestamp":1455753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 HL62594"],"award-info":[{"award-number":["RO1 HL62594"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:p>Moyamoya disease (<jats:styled-content style=\"fixed-case\">MMD<\/jats:styled-content>) 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 <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content><\/jats:italic> have been reported as a cause of <jats:styled-content style=\"fixed-case\">MMD<\/jats:styled-content> and achalasia. Probands (<jats:italic>n<\/jats:italic> = 96) from unrelated families underwent sequencing of <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content>.<\/jats:italic> Functional studies were performed to confirm the pathogenicity of identified <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content><\/jats:italic> variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content><\/jats:italic>. <jats:styled-content style=\"fixed-case\">MM041<\/jats:styled-content> was diagnosed with achalasia at 4 years of age, hypertension and <jats:styled-content style=\"fixed-case\">MMD<\/jats:styled-content> at 18 years of age. <jats:styled-content style=\"fixed-case\">MM149<\/jats:styled-content> was diagnosed with <jats:styled-content style=\"fixed-case\">MMD<\/jats:styled-content> 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, <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content><\/jats:italic> <jats:styled-content style=\"fixed-case\">Cys517Tyr<\/jats:styled-content>, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (<jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>). <jats:italic><jats:styled-content style=\"fixed-case\">GUCY1A3<\/jats:styled-content><\/jats:italic> missense and haploinsufficiency mutations disrupt <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> signaling leading to <jats:styled-content style=\"fixed-case\">MMD<\/jats:styled-content> and hypertension, with or without achalasia.<\/jats:p>","DOI":"10.1111\/cge.12739","type":"journal-article","created":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T13:18:14Z","timestamp":1453123094000},"page":"351-360","source":"Crossref","is-referenced-by-count":77,"title":["Disrupted nitric oxide signaling due to <i><scp>GUCY1A3<\/scp><\/i> mutations increases risk for moyamoya disease, achalasia and hypertension"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0824-9671","authenticated-orcid":false,"given":"S.","family":"Wallace","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine University of Texas Health Science Center  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.\u2010C.","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine University of Texas Health 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