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

Clinical Genetics
S WallaceD M Milewicz

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 acha...Continue Reading

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Citations

Feb 26, 2016·Antioxidants & Redox Signaling·Annie Beuve
Nov 2, 2016·Journal of Neurosurgery. Pediatrics·Masaki Komiyama
Oct 12, 2018·The Journal of Physiology·E N Bardsley, D J Paterson
Oct 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Henning FröhlichGudrun Rappold
Mar 26, 2019·Stroke; a Journal of Cerebral Circulation·Lou GrangeonMarkus Kraemer
Jan 29, 2019·Stroke; a Journal of Cerebral Circulation·Donna M FerrieroUNKNOWN American Heart Association Stroke Council and Council on Cardiovascular and Stroke Nursing
Jan 31, 2021·Nature Reviews. Gastroenterology & Hepatology·Beate NieslerKarl-Herbert Schäfer
Mar 16, 2021·Frontiers in Physiology·Krishan K VishnoliaJeanette Erdmann
Aug 5, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Edvaldo Balbino Alves JúniorLeônia Maria Batista
Jul 12, 2021·Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association·Santiago R UndaDavid J Altschul
Jul 21, 2021·Biomechanics and Modeling in Mechanobiology·Shaolie S HossainAnanth Annapragada
Aug 9, 2021·European Journal of Medicinal Chemistry·Kevin M GaylerEmil Martin

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