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

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. LODDER, Elisabeth M, DE NITTIS, Pasquelena, KOOPMAN, Charlotte D & Collaboration, FISH, Richard (Collab.), et al. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. American Journal of Human Genetics, 2016, vol. 99, no. 3, p. 704-710

[1]  J. Lupski,et al.  Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. , 2014, The New England journal of medicine.

[2]  Claude Bouchard,et al.  Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders , 2014 .

[3]  Mark J. Thomas,et al.  Gβ5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling , 2010, Nature Neuroscience.

[4]  Robert G. Smith,et al.  Cones Respond to Light in the Absence of Transducin β Subunit , 2013, The Journal of Neuroscience.

[5]  K. Sun,et al.  The 825C/T polymorphism of G-protein beta3 subunit gene and risk of ischaemic stroke , 2005, Journal of Human Hypertension.

[6]  K. Martemyanov,et al.  RGS6/G&bgr;5 Complex Accelerates IKACh Gating Kinetics in Atrial Myocytes and Modulates Parasympathetic Regulation of Heart Rate , 2010, Circulation research.

[7]  Long-Sheng Song,et al.  Ablation of the GNB3 gene in mice does not affect body weight, metabolism or blood pressure, but causes bradycardia. , 2014, Cellular signalling.

[8]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[9]  M. S. Almén,et al.  Evolutionary hierarchy of vertebrate-like heterotrimeric G protein families. , 2015, Molecular phylogenetics and evolution.

[10]  W. Simonds,et al.  Knockout of G protein β5 impairs brain development and causes multiple neurologic abnormalities in mice , 2011, Journal of neurochemistry.

[11]  M. Simon,et al.  A fifth member of the mammalian G-protein beta-subunit family. Expression in brain and activation of the beta 2 isotype of phospholipase C. , 1994, The Journal of biological chemistry.

[12]  A. Ghazalpour,et al.  Genetic locus on mouse chromosome 7 controls elevated heart rate. , 2012, Physiological genomics.

[13]  D. Witherow,et al.  A novel kind of G protein heterodimer: the G beta5-RGS complex. , 2003, Receptors and Channels.

[14]  J. Lupski,et al.  Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. , 2015, The Journal of clinical investigation.

[15]  C. Chen,et al.  Gβ5 Is Required for Normal Light Responses and Morphology of Retinal ON-Bipolar Cells , 2007, The Journal of Neuroscience.

[16]  T. K. Harden,et al.  Crystal structure of the multifunctional Gβ5–RGS9 complex , 2008, Nature Structural &Molecular Biology.

[17]  K. Yan,et al.  The G-protein betagamma complex. , 1998, Cellular signalling.

[18]  A. Reymond,et al.  BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies , 2015, Genome research.

[19]  J. Rosenfeld,et al.  Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures. , 2016, American journal of human genetics.

[20]  Marie E. Burns,et al.  Novel Form of Adaptation in Mouse Retinal Rods Speeds Recovery of Phototransduction , 2003, The Journal of general physiology.

[21]  Mark E. Anderson,et al.  RGS6, a Modulator of Parasympathetic Activation in Heart , 2010, Circulation research.

[22]  H. Tamai,et al.  GNB3 C825T polymorphism is associated with postural tachycardia syndrome in children , 2012, Pediatrics international : official journal of the Japan Pediatric Society.

[23]  Christophe Béroud,et al.  UMD‐Predictor: A High‐Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution , 2016, Human mutation.

[24]  J. Lupski,et al.  Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. , 2016, Endocrine-related cancer.

[25]  J. Sahel,et al.  Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness. , 2016, American journal of human genetics.

[26]  C. Raftopoulos,et al.  GHRH excess and blockade in X-LAG syndrome. , 2016, Endocrine-related cancer.

[27]  Paul M. Getty,et al.  Mutation in the guanine nucleotide-binding protein beta-3 causes retinal degeneration and embryonic mortality in chickens. , 2006, Investigative ophthalmology & visual science.

[28]  J. Chrast,et al.  TBC1D7 Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation, and Celiac Disease , 2014, Human mutation.

[29]  S. Henikoff,et al.  Predicting deleterious amino acid substitutions. , 2001, Genome research.