PUBLICATION
GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability
- Authors
- 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.
- ID
- ZDB-PUB-160816-8
- 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.
Citation
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. (2016) GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. American journal of human genetics. 99(3):704-10.
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-53.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping