Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.

TitleGermline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.
Publication TypeJournal Article
Year of Publication2016
AuthorsPetrovski, S, Küry, S, Myers, CT, Anyane-Yeboa, K, Cogné, B, Bialer, M, Xia, F, Hemati, P, Riviello, J, Mehaffey, M, Besnard, T, Becraft, E, Wadley, A, Politi, ARevah, Colombo, S, Zhu, X, Ren, Z, Andrews, I, Dudding-Byth, T, Schneider, AL, Wallace, G, Rosen, ABI, Schelley, S, Enns, GM, Corre, P, Dalton, J, Mercier, S, Latypova, X, Schmitt, S, Guzman, E, Moore, C, Bier, L, Heinzen, EL, Karachunski, P, Shur, N, Grebe, T, Basinger, A, Nguyen, JM, Bézieau, S, Wierenga, K, Bernstein, JA, Scheffer, IE, Rosenfeld, JA, Mefford, HC, Isidor, B, Goldstein, DB
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 05 05
KeywordsAdolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

Alternate JournalAm. J. Hum. Genet.
PubMed ID27108799
PubMed Central IDPMC4863562
Grant ListR01 NS069605 / NS / NINDS NIH HHS / United States
U54 HD083091 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States