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Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures
Open accessAbstract
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.
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Metadata
- Authors
- Petrovski, S., Küry, S., Myers, C. T., Anyane-Yeboa, K., Cogné, B., Bialer, M., Xia, F., Hemati, P., Riviello, J., Mehaffey, M., Besnard, T., Becraft, E., Wadley, A., Politi, A. R., Colombo, S., Zhu, X., Ren, Z., Andrews, I., Dudding-Byth, T., Schneider, A. L., Wallace, G., Rosen, A. B. I., Schelley, S., Enns, G. M., Corre, P., Dalton, J., Mercier, S., Latypova, X., Schmitt, S., Guzman, E., Moore, C., Bier, L., Heinzen, E. L., Karachunski, P., Shur, N., Grebe, T., Basinger, A., Nguyen, J. M., Bézieau, S., Wierenga, K., Bernstein, J. A., Scheffer, I. E., Rosenfeld, J. A., Mefford, H. C., Isidor, B., & Goldstein, D. B.
- Affiliations
- The Royal Melbourne Hospital (AU)
- Centre Hospitalier Universitaire de Nantes (FR)
- University of Washington (US)
- Northwell Health (US)
- Baylor College of Medicine (US)
- Columbia University (US)
- Stanford Medicine (US)
- University of Oklahoma (US)
- UNSW Sydney (AU)
- The University of Melbourne (AU)
- University of Minnesota (US)
- Albany Med Health System (US)
- Phoenix Children's Hospital (US)
- Cook Children's Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Royal Children's Hospital (AU)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Petrovski, Slavé
- Goldstein, David B.
- ORCID
- Petrovski, Slavé
- Küry, Sébastien
- Myers, Candace T.
- Cogné, Benjamin
- Xia, Fan
- Hemati, Parisa
- Riviello, James
- Besnard, Thomas
- Becraft, Emily
- Colombo, Sophie
- Zhu, Xiaolin
- Ren, Zhong
- Schneider, Amy L.
- Rosen, Aaron B.I.
- Schelley, Susan
- Enns, Gregory M.
- Corre, Pierre
- Mercier, Sandra
- Latypova, Xénia
- Schmitt, Sébastien
- Bier, Louise
- Heinzen, Erin L.
- Karachunski, Peter
- Shur, Natasha
- Nguyen, Joanne M.
- Wierenga, Klaas
- Bernstein, Jonathan A.
- Scheffer, Ingrid E.
- Rosenfeld, Jill A.
- Mefford, Heather C.
- Isidor, Bertrand
- Goldstein, David B.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 98
- Issue
- 5
- Pages
- 1001-1010
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4863562
- OpenAlex
- W2342032633
- Cited by
- 114
- References
- 32
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 15 · 2021: 14 · 2020: 12 · 2019: 19 · 2018: 8 · 2017: 11 · 2016: 5
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- National Human Genome Research Institute (UM1HG006493)
- National Institute of Neurological Disorders and Stroke (R01NS069605)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- GNB1, de novo mutations, missense mutations, Gβγ, neurodevelopmental disorders, developmental delay, hypotonia, seizures, gain-of-function, undiagnosed genetic disorders
- MeSH terms
- Adolescent, Adult, Child, Developmental Disabilities, Child, Preschool, Female, Humans, Infant, Male, Intellectual Disability, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Young Adult, Exome
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