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

Petrovski, Slavé; Küry, Sébastien; Myers, Candace T; Anyane-Yeboa, Kwame; Cogné, Benjamin; Bialer, Martin; Xia, Fan; Hemati, Parisa; Riviello, James; Mehaffey, Michele; Besnard, Thomas; Becraft, Emily; Wadley, Alexandrea; Politi, Anya Revah; Colombo, Sophie; Zhu, Xiaolin; Ren, Zhong; Andrews, Ian; Dudding-Byth, Tracy; Schneider, Amy L; Wallace, Geoffrey; Rosen, Aaron B I; Schelley, Susan; Enns, Gregory M; Corre, Pierre; Dalton, Joline; Mercier, Sandra; Latypova, Xénia; Schmitt, Sébastien; Guzman, Edwin; Moore, Christine; Bier, Louise; Heinzen, Erin L; Karachunski, Peter; Shur, Natasha; Grebe, Theresa; Basinger, Alice; Nguyen, Joanne M; Bézieau, Stéphane; Wierenga, Klaas; Bernstein, Jonathan A; Scheffer, Ingrid E; Rosenfeld, Jill A; Mefford, Heather C; Isidor, Bertrand; Goldstein, David B.
Am J Hum Genet; 98(5): 1001-1010, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108799
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, Gß. 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 Gß binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gßγ interaction (resulting in a constitutively active Gßγ) or through the disruption of residues relevant for interaction between Gßγ 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.
Selo DaSilva