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

doi:10.1016/j.ajhg.2016.03.011

. 2016 May 5;98(5):1001-1010.

doi: 10.1016/j.ajhg.2016.03.011. Epub 2016 Apr 21.

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

Slavé Petrovski¹, Sébastien Küry², Candace T Myers³, Kwame Anyane-Yeboa⁴, Benjamin Cogné², Martin Bialer⁵, Fan Xia⁶, Parisa Hemati⁷, James Riviello⁷, Michele Mehaffey³, Thomas Besnard², Emily Becraft⁸, Alexandrea Wadley⁹, Anya Revah Politi⁷, Sophie Colombo⁷, Xiaolin Zhu⁷, Zhong Ren⁷, Ian Andrews¹⁰, Tracy Dudding-Byth¹¹, Amy L Schneider¹², Geoffrey Wallace¹³; University of Washington Center for Mendelian Genomics; Aaron B I Rosen³, Susan Schelley⁸, Gregory M Enns⁸, Pierre Corre¹⁴, Joline Dalton¹⁵, Sandra Mercier², Xénia Latypova², Sébastien Schmitt², Edwin Guzman⁷, Christine Moore⁵, Louise Bier⁷, Erin L Heinzen⁷, Peter Karachunski¹⁵, Natasha Shur¹⁶, Theresa Grebe¹⁷, Alice Basinger¹⁸, Joanne M Nguyen¹⁹, Stéphane Bézieau², Klaas Wierenga⁹, Jonathan A Bernstein⁸, Ingrid E Scheffer²⁰, Jill A Rosenfeld⁶, Heather C Mefford³, Bertrand Isidor², David B Goldstein²¹

Affiliations

¹ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia. Electronic address: slavep@unimelb.edu.au.
² Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
³ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
⁴ Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
⁸ Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA.
¹⁰ School of Women's and Children's Health, University of New South Wales, Kensington, NSW 2052, Australia.
¹¹ Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia.
¹² Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia.
¹³ Department of Neurosciences, Royal Children's Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
¹⁴ Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
¹⁵ Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA.
¹⁶ Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA.
¹⁷ Phoenix Children's Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA.
¹⁸ Cook Children's Physician Network, Fort Worth, TX 76102, USA.
¹⁹ Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²⁰ Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, VIC 3050, Australia.
²¹ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA. Electronic address: dg2875@cumc.columbia.edu.

PMID: 27108799
PMCID: PMC4863562
DOI: 10.1016/j.ajhg.2016.03.011

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

Slavé Petrovski et al. Am J Hum Genet. 2016.

. 2016 May 5;98(5):1001-1010.

doi: 10.1016/j.ajhg.2016.03.011. Epub 2016 Apr 21.

Authors

Affiliations

¹ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia. Electronic address: slavep@unimelb.edu.au.
² Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
³ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle WA, 98195, USA.
⁴ Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
⁵ Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
⁸ Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Section of Genetics, Department of Pediatrics, University of Oklahoma, Oklahoma City, OK 73019, USA.
¹⁰ School of Women's and Children's Health, University of New South Wales, Kensington, NSW 2052, Australia.
¹¹ Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Priority Research Centre GrowUpWell, University of Newcastle, Callaghan, NSW 2308, Australia.
¹² Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia.
¹³ Department of Neurosciences, Royal Children's Hospital, Herston School of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
¹⁴ Service de Stomatologie, Centre Hospitalier Universitaire Nantes, Nantes 44093, France.
¹⁵ Department of Neurology, University of Minnesota, Minneapolis, MN 55454, USA.
¹⁶ Division of Genetics, Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA.
¹⁷ Phoenix Children's Hospital and Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ 85724, USA.
¹⁸ Cook Children's Physician Network, Fort Worth, TX 76102, USA.
¹⁹ Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²⁰ Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC 3081, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3050, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, VIC 3050, Australia.
²¹ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA. Electronic address: dg2875@cumc.columbia.edu.

PMID: 27108799
PMCID: PMC4863562
DOI: 10.1016/j.ajhg.2016.03.011

Abstract

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.

PubMed Disclaimer

Figures

**Figure 1**
Localization of *GNB1* Mutations (A) The distribution of the 13 mutations across *GNB1* (GenBank: NM_002074.4) shows a preferential enrichment of de novo mutations affecting exon 6. cd0020 represents the WD40 domain of GNB1. (B) Molecular representation of a heterotrimeric G protein (Gα, white; Gβ, green; Gγ, blue) is based on a crystal structure (PDB: ID 1GP2; DOI: http://dx.doi.org/10.2210/pdb1gp2/pdb). The Gβ side chains of the four residues affecting a single subject are indicated in yellow, whereas the three recurrently affected residues are indicated in red.

See this image and copyright information in PMC

Cited by

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis.
Fung JLF, Yu MHC, Huang S, Chung CCY, Chan MCY, Pajusalu S, Mak CCY, Hui VCC, Tsang MHY, Yeung KS, Lek M, Chung BHY. Fung JLF, et al. NPJ Genom Med. 2020 Sep 10;5(1):37. doi: 10.1038/s41525-020-00144-x. eCollection 2020. NPJ Genom Med. 2020. PMID: 32963807 Free PMC article.
Transcriptome 3'end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma.
Ogorodnikov A, Levin M, Tattikota S, Tokalov S, Hoque M, Scherzinger D, Marini F, Poetsch A, Binder H, Macher-Göppinger S, Probst HC, Tian B, Schaefer M, Lackner KJ, Westermann F, Danckwardt S. Ogorodnikov A, et al. Nat Commun. 2018 Dec 14;9(1):5331. doi: 10.1038/s41467-018-07580-5. Nat Commun. 2018. PMID: 30552333 Free PMC article.
Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer's Disease: An Integrated Epigenomic-Transcriptomic Analysis.
Song H, Yang J, Yu W. Song H, et al. Front Cell Dev Biol. 2022 Mar 2;9:825729. doi: 10.3389/fcell.2021.825729. eCollection 2021. Front Cell Dev Biol. 2022. PMID: 35310542 Free PMC article.
The expanding roles and mechanisms of G protein-mediated presynaptic inhibition.
Zurawski Z, Yim YY, Alford S, Hamm HE. Zurawski Z, et al. J Biol Chem. 2019 Feb 1;294(5):1661-1670. doi: 10.1074/jbc.TM118.004163. J Biol Chem. 2019. PMID: 30710014 Free PMC article. Review.
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
Redin C, Brand H, Collins RL, Kammin T, Mitchell E, Hodge JC, Hanscom C, Pillalamarri V, Seabra CM, Abbott MA, Abdul-Rahman OA, Aberg E, Adley R, Alcaraz-Estrada SL, Alkuraya FS, An Y, Anderson MA, Antolik C, Anyane-Yeboa K, Atkin JF, Bartell T, Bernstein JA, Beyer E, Blumenthal I, Bongers EM, Brilstra EH, Brown CW, Brüggenwirth HT, Callewaert B, Chiang C, Corning K, Cox H, Cuppen E, Currall BB, Cushing T, David D, Deardorff MA, Dheedene A, D'Hooghe M, de Vries BB, Earl DL, Ferguson HL, Fisher H, FitzPatrick DR, Gerrol P, Giachino D, Glessner JT, Gliem T, Grady M, Graham BH, Griffis C, Gripp KW, Gropman AL, Hanson-Kahn A, Harris DJ, Hayden MA, Hill R, Hochstenbach R, Hoffman JD, Hopkin RJ, Hubshman MW, Innes AM, Irons M, Irving M, Jacobsen JC, Janssens S, Jewett T, Johnson JP, Jongmans MC, Kahler SG, Koolen DA, Korzelius J, Kroisel PM, Lacassie Y, Lawless W, Lemyre E, Leppig K, Levin AV, Li H, Li H, Liao EC, Lim C, Lose EJ, Lucente D, Macera MJ, Manavalan P, Mandrile G, Marcelis CL, Margolin L, Mason T, Masser-Frye D, McClellan MW, Mendoza CJ, Menten B, Middelkamp S, Mikami LR, Moe E, Mohammed S, Mononen T, Mortenson ME, Moya G, Nieuwint AW, Ordulu Z, Parkash S, Pauker SP, Pereira… See abstract for full author list ➔ Redin C, et al. Nat Genet. 2017 Jan;49(1):36-45. doi: 10.1038/ng.3720. Epub 2016 Nov 14. Nat Genet. 2017. PMID: 27841880 Free PMC article.

See all "Cited by" articles

References

1. EuroEPINOMICS-RES Consortium. Epilepsy Phenome/Genome Project. Epi4K Consortium De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 2014;95:360–370. - PMC - PubMed
1. Allen A.S., Berkovic S.F., Cossette P., Delanty N., Dlugos D., Eichler E.E., Epstein M.P., Glauser T., Goldstein D.B., Han Y., Epi4K Consortium. Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221. - PMC - PubMed
1. Deciphering Developmental Disorders Study Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–228. - PMC - PubMed
1. Zhu X., Petrovski S., Xie P., Ruzzo E.K., Lu Y.F., McSweeney K.M., Ben-Zeev B., Nissenkorn A., Anikster Y., Oz-Levi D. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 2015;17:774–781. - PMC - PubMed
1. Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- GlyGen glycoinformatics resource
- The Weizmann Institute of Science GeneCards and MalaCards databases

[1] EuroEPINOMICS-RES Consortium. Epilepsy Phenome/Genome Project. Epi4K Consortium De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 2014;95:360–370. - PMC - PubMed

[2] EuroEPINOMICS-RES Consortium. Epilepsy Phenome/Genome Project. Epi4K Consortium De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 2014;95:360–370. - PMC - PubMed

[3] Allen A.S., Berkovic S.F., Cossette P., Delanty N., Dlugos D., Eichler E.E., Epstein M.P., Glauser T., Goldstein D.B., Han Y., Epi4K Consortium. Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221. - PMC - PubMed

[4] Allen A.S., Berkovic S.F., Cossette P., Delanty N., Dlugos D., Eichler E.E., Epstein M.P., Glauser T., Goldstein D.B., Han Y., Epi4K Consortium. Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221. - PMC - PubMed

[5] Deciphering Developmental Disorders Study Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–228. - PMC - PubMed

[6] Deciphering Developmental Disorders Study Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–228. - PMC - PubMed

[7] Zhu X., Petrovski S., Xie P., Ruzzo E.K., Lu Y.F., McSweeney K.M., Ben-Zeev B., Nissenkorn A., Anikster Y., Oz-Levi D. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 2015;17:774–781. - PMC - PubMed

[8] Zhu X., Petrovski S., Xie P., Ruzzo E.K., Lu Y.F., McSweeney K.M., Ben-Zeev B., Nissenkorn A., Anikster Y., Oz-Levi D. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 2015;17:774–781. - PMC - PubMed

[9] Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

[10] Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Abstract

Figures

Similar articles

Cited by

References

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases