1. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.
- Author
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Lodder EM, De Nittis P, Koopman CD, Wiszniewski W, Moura de Souza CF, Lahrouchi N, Guex N, Napolioni V, Tessadori F, Beekman L, Nannenberg EA, Boualla L, Blom NA, de Graaff W, Kamermans M, Cocciadiferro D, Malerba N, Mandriani B, Akdemir ZHC, Fish RJ, Eldomery MK, Ratbi I, Wilde AAM, de Boer T, Simonds WF, Neerman-Arbez M, Sutton VR, Kok F, Lupski JR, Reymond A, Bezzina CR, Bakkers J, and Merla G
- Subjects
- Adolescent, Animals, Child, Developmental Disabilities physiopathology, Female, GTP-Binding Protein beta Subunits deficiency, Gastroesophageal Reflux genetics, Gastroesophageal Reflux physiopathology, Gene Deletion, Heart Rate genetics, Heterozygote, Humans, Male, Muscle Hypotonia genetics, Mutation, Missense genetics, Pedigree, Phenotype, Retinal Diseases genetics, Retinal Diseases physiopathology, Seizures genetics, Syndrome, Young Adult, Zebrafish genetics, Zebrafish physiology, Zebrafish Proteins, Bradycardia genetics, Bradycardia physiopathology, Developmental Disabilities genetics, GTP-Binding Protein beta Subunits genetics, Genes, Recessive genetics, Mutation genetics, Sinoatrial Node physiopathology
- Abstract
GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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