Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease,achalasia and hypertension |
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| Authors: | S. Wallace D.‐C. Guo E. Regalado L. Mellor‐Crummey M. Bamshad D.A. Nickerson R. Dauser N. Hanchard R. Marom E. Martin V. Berka I. Sharina V. Ganesan D. Saunders S.A. Morris D.M. Milewicz |
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| Affiliation: | 1. Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA;2. Department of Genome Sciences, University of Washington, Seattle, WA, USA;3. Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA;4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;5. Neuroscience Unit, University College of London Institute of Child Health, London, UK;6. Department of Radiology, Great Ormond Street Hospital, London, UK;7. Department of Pediatrics – Cardiology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA |
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| 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. |
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| Keywords: | achalasia genetic GUCY1A3 moyamoya disease rare variants stroke |
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