GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability PMID: 27523599

Target-related Cytokines

2026-09-23

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

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].

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.