Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.
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.
Petrovski, 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, AR; Colombo, S; Zhu, X; Ren, Z; Andrews, I; Dudding-Byth, T; Schneider, AL; Wallace, G; University of Washington Center for Mendelian Genomics, ; 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
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