{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:26:31Z","timestamp":1791264391807,"version":"4.1.0"},"reference-count":132,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health; Daunia Plast and Stuppiello\u2019s Family","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein \u03b2 subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.<\/jats:p>","DOI":"10.3390\/cells8121567","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T03:16:36Z","timestamp":1575515796000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Emerging Role of G\u03b2 Subunits in Human Genetic Diseases"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0714-3314","authenticated-orcid":false,"given":"Natascia","family":"Malerba","sequence":"first","affiliation":[{"name":"Division of Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo (FG), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7144-8425","authenticated-orcid":false,"given":"Pasquelena","family":"De Nittis","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5078-928X","authenticated-orcid":false,"given":"Giuseppe","family":"Merla","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo (FG), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","article-title":"The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints","volume":"63","author":"Fredriksson","year":"2003","journal-title":"Mol. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.2042-7158.2012.01577.x","article-title":"Therapeutic implications of endothelin and thrombin G-protein-coupled receptor transactivation of tyrosine and serine\/threonine kinase cell surface receptors","volume":"65","author":"Kamato","year":"2013","journal-title":"J. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fnagi.2019.00089","article-title":"Gi\/o-Protein coupled receptors in the aging brain","volume":"11","author":"Ramos","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nrd2518","article-title":"Structural diversity of G protein-coupled receptors and significance for drug discovery","volume":"7","author":"Lagerstrom","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nrm908","article-title":"Seven-transmembrane receptors","volume":"3","author":"Pierce","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.bi.56.070187.003151","article-title":"G proteins: Transducers of receptor-generated signals","volume":"56","author":"Gilman","year":"1987","journal-title":"Annu. Rev. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1007\/s00018-008-8006-5","article-title":"G protein \u03b2\u03b3 subunits: Central mediators of G protein-coupled receptor signaling","volume":"65","author":"Smrcka","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.ajhg.2016.03.021","article-title":"Biallelic mutations in GNB3 cause a unique form of autosomal-recessive congenital stationary night blindness","volume":"98","author":"Vincent","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"28154","DOI":"10.1074\/jbc.271.45.28154","article-title":"A novel form of the G protein \u03b2 subunit G\u03b25 is specifically expressed in the vertebrate retina","volume":"271","author":"Watson","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1124\/pr.111.005603","article-title":"The expanding roles of G\u03b2\u03b3 subunits in G protein-coupled receptor signaling and drug action","volume":"65","author":"Khan","year":"2013","journal-title":"Pharm. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev-pharmtox-061008-103038","article-title":"The role of G\u03b2\u03b3 subunits in the organization, assembly, and function of GPCR signaling complexes","volume":"49","author":"Dupre","year":"2009","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ceb.2004.02.007","article-title":"Translating G protein subunit diversity into functional specificity","volume":"16","author":"Robishaw","year":"2004","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11406","DOI":"10.1073\/pnas.1936664100","article-title":"\u0392-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors","volume":"100","author":"Azzi","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yudin, Y., and Rohacs, T. (2018). Inhibitory Gi\/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics. Mol. Pain, 14.","DOI":"10.1177\/1744806918763646"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1073\/pnas.0912852107","article-title":"\u0392-arrestin- but not G protein-mediated signaling by the \u201cdecoy\u201d receptor CXCR7","volume":"107","author":"Rajagopal","year":"2010","journal-title":"PNAS Proc. Natl. Acad. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature08144","article-title":"The structure and function of G-protein-coupled receptors","volume":"459","author":"Rosenbaum","year":"2009","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18706","DOI":"10.1073\/pnas.0504778102","article-title":"Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells","volume":"102","author":"Nobles","year":"2005","journal-title":"PNAS Proc. Natl Acad Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1038\/sj.bjp.0706405","article-title":"Heterotrimeric G-proteins: A short history","volume":"147","author":"Milligan","year":"2006","journal-title":"Br. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1073\/pnas.94.2.428","article-title":"RGS4 and GAIP are GTPase-activating proteins for Gq\u03b1 and block activation of phospholipase C\u03b2 by \u03b3-thio-GTP-Gq\u03b1","volume":"94","author":"Hepler","year":"1997","journal-title":"PNAS Proc. Natl. Acad. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1126\/science.280.5372.2109","article-title":"P115 RhoGEF, a GTPase activating protein for G\u03b112 and G\u03b113","volume":"280","author":"Kozasa","year":"1998","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/383175a0","article-title":"RGS10 is a selective activator of G\u03b1i GTPase activity","volume":"383","author":"Hunt","year":"1996","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0092-8674(00)80117-8","article-title":"GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein \u03b1 subunits","volume":"86","author":"Berman","year":"1996","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev.pharmtox.40.1.235","article-title":"The regulator of G protein signaling family","volume":"40","author":"Zheng","year":"2000","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0092-8674(95)90407-7","article-title":"Heterotrimeric G proteins: Organizers of transmembrane signals","volume":"80","author":"Neer","year":"1995","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1006\/geno.1999.5992","article-title":"The G protein subunit gene families","volume":"62","author":"Downes","year":"1999","journal-title":"Genomics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"34429","DOI":"10.1074\/jbc.273.51.34429","article-title":"Differential activity of the G protein \u03b25\u03b32 subunit at receptors and effectors","volume":"273","author":"Lindorfer","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0898-6568(98)00006-0","article-title":"The G-protein \u03b2\u03b3 complex","volume":"10","author":"Gautam","year":"1998","journal-title":"Cell Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16386","DOI":"10.1074\/jbc.M900800200","article-title":"Role of molecular chaperones in G protein \u03b25\/regulator of G protein signaling dimer assembly and G protein \u03b2\u03b3 dimer specificity","volume":"284","author":"Howlett","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22150","DOI":"10.1016\/S0021-9258(17)31768-4","article-title":"A fifth member of the mammalian G-protein \u03b2-subunit family. Expression in brain and activation of the \u03b22 isotype of phospholipase C","volume":"269","author":"Watson","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1007\/PL00000838","article-title":"WD-repeat proteins: Structure characteristics, biological function, and their involvement in human diseases","volume":"58","author":"Li","year":"2001","journal-title":"Cell Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/379369a0","article-title":"Crystal structure of a G-protein \u03b2\u03b3 dimer at 2.1A resolution","volume":"379","author":"Sondek","year":"1996","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s10930-018-9785-7","article-title":"WD40 repeat proteins: Signalling scaffold with diverse functions","volume":"37","author":"Jain","year":"2018","journal-title":"Protein J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D619","DOI":"10.1093\/nar\/gkw1033","article-title":"Genenames.org: the HGNC and VGNC resources in 2017","volume":"45","author":"Yates","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"UniProt Consortium (2019). UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res., 47, D506\u2013D515.","DOI":"10.1093\/nar\/gky1049"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1212\/NXG.0000000000000106","article-title":"Novel GNB1 missense mutation in a patient with generalized dystonia, hypotonia, and intellectual disability","volume":"2","author":"Steinrucke","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Endo, W., Ikemoto, S., Togashi, N., Miyabayashi, T., Nakajima, E., Hamano, S.I., Shibuya, M., Sato, R., Takezawa, Y., and Okubo, Y. (2019). Phenotype-genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms. Brain Dev.","DOI":"10.1016\/j.braindev.2019.10.006"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/ajmg.a.38026","article-title":"Acute lymphoblastic leukemia in a child with a de novo germline gnb1 mutation","volume":"173","author":"Brett","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.ajhg.2016.03.011","article-title":"Germline de novo mutations in GNB1 cause severe neurodevelopmental disability, hypotonia, and seizures","volume":"98","author":"Petrovski","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1002\/mds.27708","article-title":"Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation","volume":"34","author":"Jones","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_40","first-page":"1078","article-title":"Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans","volume":"26","author":"Lohmann","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1002\/ajmg.a.40472","article-title":"Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature","volume":"176","author":"Hemati","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ejmg.2017.11.010","article-title":"Novel GNB1 de novo mutation in a patient with neurodevelopmental disorder and cutaneous mastocytosis: Clinical report and literature review","volume":"61","author":"Szczaluba","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1002\/ajmg.a.33516","article-title":"Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions","volume":"152A","author":"Rosenfeld","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.genet.34.1.297","article-title":"Molecular mechanisms for constitutional chromosomal rearrangements in humans","volume":"34","author":"Shaffer","year":"2000","journal-title":"Annu. Rev. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1002\/dvdy.22256","article-title":"Neural tube defects and impaired neural progenitor cell proliferation in G\u03b21-deficient mice","volume":"239","author":"Okae","year":"2010","journal-title":"Dev. Dyn."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1126\/science.280.5367.1271","article-title":"Molecular basis for interactions of G protein \u03b2\u03b3 subunits with effectors","volume":"280","author":"Ford","year":"1998","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1161\/CIRCRESAHA.116.310112","article-title":"A mutation in the G-protein gene GNB2 causes familial sinus node and atrioventricular conduction dysfunction","volume":"120","author":"Stallmeyer","year":"2017","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nature12241","article-title":"X-ray structure of the mammalian GIRK2-\u03b2\u03b3 G-protein complex","volume":"498","author":"Whorton","year":"2013","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"H445","DOI":"10.1152\/ajpheart.00565.2001","article-title":"Impaired parasympathetic heart rate control in mice with a reduction of functional G protein \u03b2\u03b3-subunits","volume":"282","author":"Gehrmann","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/325321a0","article-title":"The \u03b2\u03b3 subunits of GTP-binding proteins activate the muscarinic K+ channel in heart","volume":"325","author":"Logothetis","year":"1987","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e002238","DOI":"10.1161\/CIRCGEN.118.002238","article-title":"Familial sinus node disease caused by a gain of GIRK (G-protein activated inwardly rectifying K+ channel) channel function","volume":"12","author":"Kuss","year":"2019","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nature19356","article-title":"High-throughput discovery of novel developmental phenotypes","volume":"537","author":"Dickinson","year":"2016","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Fukuda, T., Hiraide, T., Yamoto, K., Nakashima, M., Kawai, T., Yanagi, K., Ogata, T., and Saitsu, H. (2019). Exome reports A de novo GNB2 variant associated with global developmental delay, intellectual disability, and dysmorphic features. Eur. J. Med. Genet., 103804.","DOI":"10.1016\/j.ejmg.2019.103804"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ydbio.2017.05.024","article-title":"G\u03b21 is required for neutrophil migration in zebrafish","volume":"428","author":"Ke","year":"2017","journal-title":"Dev. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/S0960-9822(03)00334-8","article-title":"Heterotrimeric G proteins regulate daughter cell size asymmetry in Drosophila neuroblast divisions","volume":"13","author":"Fuse","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E12","DOI":"10.1371\/journal.pbio.0000012","article-title":"Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions","volume":"1","author":"Simmer","year":"2003","journal-title":"PLoS Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1080\/02763869.2019.1548896","article-title":"WormBase: A model organism database","volume":"38","author":"Hurd","year":"2019","journal-title":"Med. Ref. Serv. Q"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1016\/j.cellsig.2014.07.030","article-title":"Ablation of the GNB3 gene in mice does not affect body weight, metabolism or blood pressure, but causes bradycardia","volume":"26","author":"Ye","year":"2014","journal-title":"Cell Signal."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ozdemir, A.C., Wynn, G.M., Vester, A., Weitzmann, M.N., Neigh, G.N., Srinivasan, S., and Rudd, M.K. (2017). GNB3 overexpression causes obesity and metabolic syndrome. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188763"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14990","DOI":"10.1073\/pnas.1305999110","article-title":"Mouse model implicates GNB3 duplication in a childhood obesity syndrome","volume":"110","author":"Goldlust","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lagman, D., Callado-Perez, A., Franzen, I.E., Larhammar, D., and Abalo, X.M. (2015). Transducin duplicates in the zebrafish retina and pineal complex: Differential specialisation after the teleost tetraploidisation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121330"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1096\/fj.11-190157","article-title":"Targeted deletion of one or two copies of the G protein \u03b2 subunit G\u03b25 gene has distinct effects on body weight and behavior in mice","volume":"25","author":"Wang","year":"2011","journal-title":"FASEB J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1111\/j.1471-4159.2011.07457.x","article-title":"Knockout of G protein \u03b25 impairs brain development and causes multiple neurologic abnormalities in mice","volume":"119","author":"Zhang","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00213-011-2409-y","article-title":"G\u03b25-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems","volume":"219","author":"Xie","year":"2012","journal-title":"Psychopharmacology (Berl)"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6604","DOI":"10.1073\/pnas.0631825100","article-title":"Instability of GGL domain-containing RGS proteins in mice lacking the G protein \u03b2-subunit G\u03b25","volume":"100","author":"Chen","year":"2003","journal-title":"PNAS Proc. Natl. Acad. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.ajhg.2016.06.025","article-title":"GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability","volume":"99","author":"Lodder","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"D759","DOI":"10.1093\/nar\/gky1003","article-title":"FlyBase 2.0: The next generation","volume":"47","author":"Thurmond","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0960-9822(01)00074-4","article-title":"Eat-11 encodes GPB-2, a G\u03b25 ortholog that interacts with Go\u03b1 and Gq\u03b1 to regulate C. elegans behavior","volume":"11","author":"Robatzek","year":"2001","journal-title":"Curr. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1001\/jamaophthalmol.2016.1543","article-title":"Recessive retinopathy consequent on mutant G-protein \u03b2 subunit 3 (GNB3)","volume":"134","author":"Arno","year":"2016","journal-title":"JAMA Ophthalmol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"14166","DOI":"10.1038\/s41598-019-50573-7","article-title":"Genome-wide association study and whole-genome sequencing identify a deletion in LRIT3 associated with canine congenital stationary night blindness","volume":"9","author":"Das","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.preteyeres.2014.09.001","article-title":"Congenital stationary night blindness: An analysis and update of genotype-phenotype correlations and pathogenic mechanisms","volume":"45","author":"Zeitz","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.neuroscience.2010.05.081","article-title":"The pattern of expression of guanine nucleotide-binding protein \u03b23 in the retina is conserved across vertebrate species","volume":"169","author":"Ritchey","year":"2010","journal-title":"Neuroscience"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"24776","DOI":"10.1016\/S0021-9258(18)35831-9","article-title":"A third form of the G protein \u03b2 subunit. 1. Immunochemical identification and localization to cone photoreceptors","volume":"267","author":"Lee","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"10882","DOI":"10.1073\/pnas.89.22.10882","article-title":"Retinal rods and cones have distinct G protein \u03b2 and \u03b3 subunits","volume":"89","author":"Peng","year":"1992","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5182","DOI":"10.1523\/JNEUROSCI.5204-12.2013","article-title":"Cones respond to light in the absence of transducin \u03b2 subunit","volume":"33","author":"Nikonov","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11343","DOI":"10.1523\/JNEUROSCI.1436-12.2012","article-title":"G\u03b23 is required for normal light ON responses and synaptic maintenance","volume":"32","author":"Dhingra","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4714","DOI":"10.1167\/iovs.06-0292","article-title":"Mutation in the guanine nucleotide-binding protein \u03b2-3 causes retinal degeneration and embryonic mortality in chickens","volume":"47","author":"Tummala","year":"2006","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/ng0198-45","article-title":"Association of a human G-protein \u03b23 subunit variant with hypertension","volume":"18","author":"Siffert","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.repc.2017.09.018","article-title":"The genetic variant C825T of the \u03b23 subunit of G protein is associated with hypertension in a Portuguese population","volume":"37","author":"Sousa","year":"2018","journal-title":"Rev. Port. Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/jhh.2017.31","article-title":"Association of G-protein \u03b23 subunit C825T polymorphism with essential hypertension: Evidence from 63,729 subjects","volume":"31","author":"Rong","year":"2017","journal-title":"J. Hum. Hypertens."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/S0008-6363(00)00292-3","article-title":"Association between a polymorphism in the G protein \u03b23 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction","volume":"49","author":"Hengstenberg","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.4314\/ahs.v17i4.14","article-title":"Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects","volume":"17","author":"Moselhy","year":"2017","journal-title":"Afr. Health Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s13205-016-0572-x","article-title":"Role of GNB3, NET, KCNJ11, TCF7L2 and GRL genes single nucleotide polymorphism in the risk prediction of type 2 diabetes mellitus","volume":"6","author":"Rizvi","year":"2016","journal-title":"3 Biotech."},{"key":"ref_84","first-page":"155","article-title":"A longitudinal study of the association between the GNB3 C825T polymorphism and metabolic disturbance in bipolar II patients treated with valproate","volume":"17","author":"Chen","year":"2017","journal-title":"Pharm. J."},{"key":"ref_85","first-page":"1242","article-title":"Association of metabolic syndrome components with the genotypes of the C825T polymorphism in the G protein \u03b23-subunit gene (GNB3)","volume":"71","author":"Prystupa","year":"2018","journal-title":"Wiadomosci Lekarskie"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ma, J., Wang, L., Yang, Y., Qiao, Z., Fang, D., Qiu, X., Yang, X., Zhu, X., He, J., and Pan, H. (2017). GNB3 and CREB1 gene polymorphisms combined with negative life events increase susceptibility to major depression in a Chinese Han population. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170994"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1097\/00001756-200006260-00018","article-title":"Evidence for an association between a G-protein \u03b23-gene variant with depression and response to antidepressant treatment","volume":"11","author":"Zill","year":"2000","journal-title":"Neuroreport"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"200","DOI":"10.30773\/pi.2017.09.21","article-title":"Association of G-protein \u03b23 subunit C825T polymorphism with seasonal variations in mood and behavior","volume":"15","author":"Nam","year":"2018","journal-title":"Psychiatry Investig."},{"key":"ref_89","first-page":"5037254","article-title":"The C825T polymorphism of the G-protein \u03b23 gene as a risk factor for functional dyspepsia: A meta-analysis","volume":"2016","author":"Song","year":"2016","journal-title":"Gastroenterol. Res. Pr."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Triantafyllou, K., Kourikou, A., Gazouli, M., Karamanolis, G.P., and Dimitriadis, G.D. (2017). Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms in the Greek population. Neurogastroenterol. Motil., 29.","DOI":"10.1111\/nmo.12913"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1161\/01.STR.32.4.822","article-title":"G-protein \u03b23 subunit and \u03b1-adducin polymorphisms and risk of subclinical and clinical stroke","volume":"32","author":"Morrison","year":"2001","journal-title":"Stroke"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/sj.jhh.1001883","article-title":"The 825C\/T polymorphism of G-protein \u03b23 subunit gene and risk of ischaemic stroke","volume":"19","author":"Zhang","year":"2005","journal-title":"J. Hum. Hypertens."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.ahj.2004.03.024","article-title":"C825T polymorphism of the G-protein \u03b23 subunit gene and atrial fibrillation: Association of the TT genotype with a reduced risk for atrial fibrillation","volume":"148","author":"Schreieck","year":"2004","journal-title":"Am. Heart J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/10641963.2016.1210621","article-title":"Association of G-protein \u03b23 subunit gene C825T polymorphism with cardiac and cerebrovascular events in Chinese hypertensive patients","volume":"39","author":"Zhu","year":"2017","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/09674845.2018.1527802","article-title":"Association of SDF1\u03b2 (G801A) and GNB3 (C825T) polymorphisms with the incidence and severity of coronary artery disease","volume":"76","author":"Eba","year":"2019","journal-title":"Br. J. Biomed. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/j.1442-200X.2012.03707.x","article-title":"GNB3 C825T polymorphism is associated with postural tachycardia syndrome in children","volume":"54","author":"Nakao","year":"2012","journal-title":"Pediatr. Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.atherosclerosis.2014.08.025","article-title":"GNB3 gene 825 TT variant predicts hard coronary events in the population-based Heinz Nixdorf Recall study","volume":"237","author":"Frey","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1161\/01.STR.0000058159.63950.EA","article-title":"Associations of a human G protein \u03b23 subunit dimorphism with insulin resistance and carotid atherosclerosis","volume":"34","author":"Wascher","year":"2003","journal-title":"Stroke"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/ajh.2011.257","article-title":"The C825T GNB3 polymorphism, independent of blood pressure, predicts cerebrovascular risk at a population level","volume":"25","author":"Casiglia","year":"2012","journal-title":"Am. J. Hypertens."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13039-018-0363-7","article-title":"Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity","volume":"11","author":"Varela","year":"2018","journal-title":"Mol. Cytogenet."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ajhg.2013.01.014","article-title":"Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease","volume":"92","author":"Soong","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.nmd.2016.09.010","article-title":"Confirmation of the GNB4 gene as causal for Charcot-Marie-Tooth disease by a novel de novo mutation in a Czech patient","volume":"27","author":"Lassuthova","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ejmg.2017.06.006","article-title":"A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit \u03b2-4 in a Japanese family with autosomal dominant motor and sensory neuropathy","volume":"60","author":"Miura","year":"2017","journal-title":"Eur. J. Med. Genet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/S0969-2126(98)00117-8","article-title":"Structural basis of activity and subunit recognition in G protein heterotrimers","volume":"6","author":"Wall","year":"1998","journal-title":"Structure"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(00)81376-8","article-title":"Crystal structure at 2.4 angstroms resolution of the complex of transducin \u03b2\u03b3 and its regulator, phosducin","volume":"87","author":"Gaudet","year":"1996","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.cellsig.2015.04.007","article-title":"G\u03b24\u03b31 as a modulator of M3 muscarinic receptor signalling and novel roles of G\u03b21 subunits in the modulation of cellular signalling","volume":"27","author":"Khan","year":"2015","journal-title":"Cell Signal."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1161\/CIRCULATIONAHA.108.804369","article-title":"Molecular architecture of the human sinus node: Insights into the function of the cardiac pacemaker","volume":"119","author":"Chandler","year":"2009","journal-title":"Circulation"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1152\/physiolgenomics.00085.2001","article-title":"Cloning, tissue distribution, and functional expression of the human G protein \u03b24-subunit","volume":"8","author":"Ikeda","year":"2002","journal-title":"Physiol. Genom."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1172\/JCI200415925","article-title":"Differential subunit composition of the G protein-activated inward-rectifier potassium channel during cardiac development","volume":"114","author":"Fleischmann","year":"2004","journal-title":"J. Clin. Invest."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0014-5793(03)00441-1","article-title":"The human G protein \u03b24 subunit: Gene structure, expression, G\u03b3 and effector interaction","volume":"544","author":"Rosskopf","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/ng.2610","article-title":"Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders","volume":"45","author":"Eijgelsheim","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1152\/physiolgenomics.00041.2012","article-title":"Genetic locus on mouse chromosome 7 controls elevated heart rate","volume":"44","author":"Smolock","year":"2012","journal-title":"Physiol. Genom."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e42150","DOI":"10.7554\/eLife.42150","article-title":"Structural organization of a major neuronal G protein regulator, the RGS7-G\u03b25-R7BP complex","volume":"7","author":"Patil","year":"2018","journal-title":"eLIFE"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"ra63","DOI":"10.1126\/scisignal.2002922","article-title":"The complex of G protein regulator RGS9-2 and G\u03b25 controls sensitization and signaling kinetics of type 5 adenylyl cyclase in the striatum","volume":"5","author":"Xie","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_115","first-page":"205","article-title":"A novel kind of G protein heterodimer: The G \u03b25-RGS complex","volume":"9","author":"Witherow","year":"2003","journal-title":"Recept. Channels"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0028-3908(03)00149-7","article-title":"The G\u03b25 subunit that associates with the R7 subfamily of RGS proteins regulates mu-opioid effects","volume":"45","author":"Garzon","year":"2003","journal-title":"Neuropharmacology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s12020-012-9611-5","article-title":"Expression of the G\u03b25\/R7-RGS protein complex in pituitary and pancreatic islet cells","volume":"42","author":"Nini","year":"2012","journal-title":"Endocrine"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/S0006-2952(01)00633-5","article-title":"G\u03b3-like (GGL) domains: New frontiers in G-protein signaling and \u03b2-propeller scaffolding","volume":"61","author":"Sondek","year":"2001","journal-title":"Biochem. Pharm."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nn.2549","article-title":"G\u03b25 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling","volume":"13","author":"Xie","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Shao, Z., Tumber, A., Maynes, J., Tavares, E., Kannu, P., Heon, E., and Vincent, A. (2019). Unique retinal signaling defect in GNB5-related disease. Doc. Ophthalmol.","DOI":"10.1007\/s10633-019-09735-1"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C.F., Fung, J., Chung, B., Fung, C.W., and Mignot, C. (2019). The epileptology of GNB5 encephalopathy. Epilepsia, 60.","DOI":"10.1111\/epi.16372"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3389\/fgene.2018.00626","article-title":"A NGS-targeted autism\/ID Panel reveals compound heterozygous GNB5 variants in a novel patient","volume":"9","author":"Malerba","year":"2018","journal-title":"Front. Genet."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1111\/cge.13194","article-title":"Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants","volume":"93","author":"Vernon","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.seizure.2017.06.019","article-title":"Familial early infantile epileptic encephalopathy and cardiac conduction disorder: A rare cause of SUDEP in infancy","volume":"50","author":"Turkdogan","year":"2017","journal-title":"Seizure"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s13059-016-1061-6","article-title":"GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition","volume":"17","author":"Shamseldin","year":"2016","journal-title":"Genome Biol."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Veerman, C.C., Mengarelli, I., Koopman, C.D., Wilders, R., van Amersfoorth, S.C., Bakker, D., Wolswinkel, R., Hababa, M., de Boer, T.P., and Guan, K. (2019). Genetic variation in GNB5 causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (IK,ACh). Dis. Model. Mech., 12.","DOI":"10.1242\/dmm.037994"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1085\/jgp.200308938","article-title":"Novel form of adaptation in mouse retinal rods speeds recovery of phototransduction","volume":"122","author":"Krispel","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Tian, M., Zallocchi, M., Wang, W., Chen, C.K., Palczewski, K., Delimont, D., Cosgrove, D., and Peng, Y.W. (2013). Light-induced translocation of RGS9-1 and G\u03b25L in mouse rod photoreceptors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058832"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"14199","DOI":"10.1523\/JNEUROSCI.4934-07.2007","article-title":"G\u03b25 is required for normal light responses and morphology of retinal ON-bipolar cells","volume":"27","author":"Rao","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Kulkarni, K., Xie, X., Marron Fernandez de Velasco, E., Anderson, A., Martemyanov, K.A., Wickman, K., and Tolkacheva, E.G. (2018). Correction: The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200553"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1161\/CIRCRESAHA.110.224212","article-title":"RGS6\/G\u03b25 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate","volume":"107","author":"Posokhova","year":"2010","journal-title":"Circ. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1074\/jbc.M111.297218","article-title":"Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling","volume":"287","author":"Maity","year":"2012","journal-title":"J. Biol. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:10Z","timestamp":1760190010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":132,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121567"],"URL":"https:\/\/doi.org\/10.3390\/cells8121567","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]}}}