GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Elisabeth M. Lodder, Pasquelena De Nittis, Charlotte D. Koopman, Wojciech Wiszniewski, Carolina Fischinger Moura de Souza, Najim Lahrouchi, Nicolas Guex, Valerio Napolioni, Federico Tessadori, Leander Beekman, Eline A. Nannenberg, Lamiae Boualla, Nico A. Blom, Wim de Graaff, Maarten Kamermans, Dario Cocciadiferro, Natascia Malerba, Barbara Mandriani, Zeynep Hande Coban Akdemir, Richard J. Fish & 13 others Mohammad K. Eldomery, Ilham Ratbi, Arthur A M Wilde, Teun de Boer, William F. Simonds, Marguerite Neerman-Arbez, V. Reid Sutton, Fernando Kok, James R. Lupski, Alexandre Reymond, Connie R. Bezzina, Jeroen Bakkers, Giuseppe Merla

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
DOIs
Publication statusAccepted/In press - May 18 2016

Fingerprint

Muscle Hypotonia
Bradycardia
GTP-Binding Proteins
Mutation
Heart Rate
Language Development Disorders
Sick Sinus Syndrome
Retinal Diseases
Eye Diseases
Protein Subunits
Zebrafish
Heterozygote
Gastroesophageal Reflux
Intellectual Disability
Stomach
Seizures
Alleles
Phenotype

Keywords

  • G-protein signaling
  • Heart rate
  • Hypotonia
  • Intellectual disability
  • Parasympathetic system
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. / Lodder, Elisabeth M.; De Nittis, Pasquelena; Koopman, Charlotte D.; Wiszniewski, Wojciech; Moura de Souza, Carolina Fischinger; Lahrouchi, Najim; Guex, Nicolas; Napolioni, Valerio; Tessadori, Federico; Beekman, Leander; Nannenberg, Eline A.; Boualla, Lamiae; Blom, Nico A.; de Graaff, Wim; Kamermans, Maarten; Cocciadiferro, Dario; Malerba, Natascia; Mandriani, Barbara; Akdemir, Zeynep Hande Coban; Fish, Richard J.; Eldomery, Mohammad K.; Ratbi, Ilham; Wilde, Arthur A M; de Boer, Teun; Simonds, William F.; Neerman-Arbez, Marguerite; Sutton, V. Reid; Kok, Fernando; Lupski, James R.; Reymond, Alexandre; Bezzina, Connie R.; Bakkers, Jeroen; Merla, Giuseppe.

In: American Journal of Human Genetics, 18.05.2016.

Research output: Contribution to journalArticle

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 & Merla, G 2016, 'GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability', American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2016.06.025
Lodder, Elisabeth M. ; De Nittis, Pasquelena ; Koopman, Charlotte D. ; Wiszniewski, Wojciech ; Moura de Souza, Carolina Fischinger ; Lahrouchi, Najim ; Guex, Nicolas ; Napolioni, Valerio ; Tessadori, Federico ; Beekman, Leander ; Nannenberg, Eline A. ; Boualla, Lamiae ; Blom, Nico A. ; de Graaff, Wim ; Kamermans, Maarten ; Cocciadiferro, Dario ; Malerba, Natascia ; Mandriani, Barbara ; Akdemir, Zeynep Hande Coban ; Fish, Richard J. ; Eldomery, Mohammad K. ; Ratbi, Ilham ; Wilde, Arthur A M ; de Boer, Teun ; Simonds, William F. ; Neerman-Arbez, Marguerite ; Sutton, V. Reid ; Kok, Fernando ; Lupski, James R. ; Reymond, Alexandre ; Bezzina, Connie R. ; Bakkers, Jeroen ; Merla, Giuseppe. / GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. In: American Journal of Human Genetics. 2016.
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AU - Lodder, Elisabeth M.

AU - De Nittis, Pasquelena

AU - Koopman, Charlotte D.

AU - Wiszniewski, Wojciech

AU - Moura de Souza, Carolina Fischinger

AU - Lahrouchi, Najim

AU - Guex, Nicolas

AU - Napolioni, Valerio

AU - Tessadori, Federico

AU - Beekman, Leander

AU - Nannenberg, Eline A.

AU - Boualla, Lamiae

AU - Blom, Nico A.

AU - de Graaff, Wim

AU - Kamermans, Maarten

AU - Cocciadiferro, Dario

AU - Malerba, Natascia

AU - Mandriani, Barbara

AU - Akdemir, Zeynep Hande Coban

AU - Fish, Richard J.

AU - Eldomery, Mohammad K.

AU - Ratbi, Ilham

AU - Wilde, Arthur A M

AU - de Boer, Teun

AU - Simonds, William F.

AU - Neerman-Arbez, Marguerite

AU - Sutton, V. Reid

AU - Kok, Fernando

AU - Lupski, James R.

AU - Reymond, Alexandre

AU - Bezzina, Connie R.

AU - Bakkers, Jeroen

AU - Merla, Giuseppe

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