- Title
- Germline de novo mutations in GNB1 cause severe neurodevelopmental disability, hypotonia, and seizures
- Creator
- Petrovski, Slavé; Kury, Sébastien; Besnard, Thomas; Becraft, Emily; Wadley, Alexandrea; Politi, Anya Revah; Colombo, Sophie; Zhu, Xiaolin; Ren, Zhong; Andrews, Ian; Dudding-Byth, Tracy; Schneider, Amy L.; Myers, Candace T.; Anyane-Yeboa, Kwame; Cogné, Benjamin; Bialer, Martin; Xia, Fan; Hemati, Parisa; Riviello, James; Mehaffey, Michele
- Relation
- American Journal of Human Genetics Vol. 98, Issue 5, p. 1001-1010
- Publisher Link
- http://dx.doi.org/10.1016/j.ajhg.2016.03.011
- Publisher
- Cell Press
- Resource Type
- journal article
- Date
- 2016
- Description
- 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 x 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.
- Subject
- germline de novo mutations; GNB1; neurodevelopmental disabilities; hypotonia; seizures
- Identifier
- http://hdl.handle.net/1959.13/1323549
- Identifier
- uon:24835
- Identifier
- ISSN:0002-9297
- Language
- eng
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