2. Academic Validation
  3. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

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

  • Am J Hum Genet. 2016 Sep 1;99(3):704-710. doi: 10.1016/j.ajhg.2016.06.025.
Elisabeth M Lodder 1,  Pasquelena De Nittis 2,  Charlotte D Koopman 3,  Wojciech Wiszniewski 4,  Carolina Fischinger Moura de Souza 5,  Najim Lahrouchi 1,  Nicolas Guex 6,  Valerio Napolioni 7,  Federico Tessadori 8,  Leander Beekman 1,  Eline A Nannenberg 9,  Lamiae Boualla 10,  Nico A Blom 11,  Wim de Graaff 12,  Maarten Kamermans 13,  Dario Cocciadiferro 14,  Natascia Malerba 14,  Barbara Mandriani 15,  Zeynep Hande Coban Akdemir 4,  Richard J Fish 16,  Mohammad K Eldomery 4,  Ilham Ratbi 10,  Arthur A M Wilde 1,  Teun de Boer 17,  William F Simonds 18,  Marguerite Neerman-Arbez 16,  V Reid Sutton 19,  Fernando Kok 20,  James R Lupski 21,  Alexandre Reymond 22,  Connie R Bezzina 1,  Jeroen Bakkers 23,  Giuseppe Merla 24
Affiliations

Affiliations

  • 1 Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 2 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy.
  • 3 Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Medical Genetics Service, Hospital de Clinicas de Porto Alegre, 2350 Porto Alegre, Brazil.
  • 6 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • 7 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
  • 8 Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
  • 9 Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 10 Centre de Génomique Humaine, Faculté de Médecine et Pharmacie, Mohammed V University of Rabat, 8007, Rabat, Morocco.
  • 11 Department of Pediatric Cardiology, Emma Children's Hospital, Academic Medical Centre, 1105 AZ Amsterdam, the Netherlands.
  • 12 Retinal Signal Processing Lab, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands.
  • 13 Retinal Signal Processing Lab, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands; Department of Genome Analysis, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 14 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy; PhD Program in Experimental and Regenerative Medicine, Faculty of Medicine, University of Foggia, 71121 Foggia, Italy.
  • 15 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy; PhD Program in Molecular Genetics Applied to Medical Sciences, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
  • 16 Department of Genetic Medicine and Development, University Medical Centre (CMU), 1211 Geneva, Switzerland.
  • 17 Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands.
  • 18 Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892-2560, USA.
  • 19 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 20 Child Neurology Division, Department of Neurology, School of Medicine, University of Sao Paulo, 01246903 Sao Paulo, Brazil.
  • 21 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 22 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
  • 23 Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Hubrecht Institute- Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands. Electronic address: [email protected].
  • 24 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address: [email protected].
PMID: 27523599 DOI: 10.1016/j.ajhg.2016.06.025
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.

Keywords

G-protein signaling; heart rate; hypotonia; intellectual disability; parasympathetic system; whole-exome sequencing.

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