title: 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.
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: S
authors.identifier: 0000-0003-0824-9671
authors.initials: S
authors.lastname: Wallace
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: D-C
authors.initials: DC
authors.lastname: Guo
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Regalado
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mellor-Crummey
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dauser
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hanchard
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Marom
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Martin
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Berka
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Sharina
authors.affiliation: Neuroscience Unit, University College of London Institute of Child Health, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Ganesan
authors.affiliation: Department of Radiology, Great Ormond Street Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Department of Pediatrics - Cardiology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Morris
authors.affiliation: Division of Medical Genetics, Cardiology, and Hematology, Department of Internal Medicine, University of Texas Health Science Center, Houston, TX, USA. Dianna.M.Milewicz@uth.tmc.edu.
authors.forename: D M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004931:Esophageal Achalasia / Q000235:genetics*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics*; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism*; D017711:Nonlinear Dynamics; D012044:Regression Analysis; D061987:Sf9 Cells; D015398:Signal Transduction / Q000235:genetics*; D000071756:Soluble Guanylyl Cyclase / Q000737:chemistry / Q000235:genetics*
chemical_list: C000605661:GUCY1A1 protein, human; D009569:Nitric Oxide; D000071756:Soluble Guanylyl Cyclase
keywords: GUCY1A3; achalasia; genetic; moyamoya disease; rare variants; stroke