ZFIN ID: ZDB-PUB-160816-8
GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability
Lodder, E.M., De Nittis, P., Koopman, C.D., Wiszniewski, W., Moura de Souza, C.F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E.A., Boualla, L., Blom, N.A., de Graaff, W., Kamermans, M., Cocciadiferro, D., Malerba, N., Mandriani, B., Akdemir, Z.H., Fish, R.J., Eldomery, M.K., Ratbi, I., Wilde, A.A., de Boer, T., Simonds, W.F., Neerman-Arbez, M., Sutton, V.R., Kok, F., Lupski, J.R., Reymond, A., Bezzina, C.R., Bakkers, J., Merla, G.
Date: 2016
Source: American journal of human genetics   99(3): 704-10 (Journal)
Registered Authors: Bakkers, Jeroen, Fish, Richard, Kamermans, Maarten, Neerman-Arbez, Marguerite
Keywords: G-protein signaling, heart rate, hypotonia, intellectual disability, parasympathetic system, whole-exome sequencing
MeSH Terms:
  • Adolescent
  • Animals
  • Bradycardia/genetics*
  • Bradycardia/physiopathology*
  • Child
  • Developmental Disabilities/genetics*
  • Developmental Disabilities/physiopathology
  • Female
  • GTP-Binding Protein beta Subunits/deficiency
  • GTP-Binding Protein beta Subunits/genetics*
  • Gastroesophageal Reflux/genetics
  • Gastroesophageal Reflux/physiopathology
  • Gene Deletion
  • Genes, Recessive/genetics*
  • Heart Rate/genetics
  • Heterozygote
  • Humans
  • Male
  • Muscle Hypotonia/genetics
  • Mutation/genetics*
  • Mutation, Missense/genetics
  • Pedigree
  • Phenotype
  • Retinal Diseases/genetics
  • Retinal Diseases/physiopathology
  • Seizures/genetics
  • Sinoatrial Node/physiopathology*
  • Syndrome
  • Young Adult
  • Zebrafish/genetics
  • Zebrafish/physiology
PubMed: 27523599 Full text @ Am. J. Hum. Genet.
FIGURES
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.
ADDITIONAL INFORMATION