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Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

BACKGROUND: GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of...

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Autores principales: Schultz‐Rogers, Laura, Masuho, Ikuo, Pinto e Vairo, Filippo, Schmitz, Christopher T., Schwab, Tanya L., Clark, Karl J., Gunderson, Lauren, Pichurin, Pavel N., Wierenga, Klaas, Martemyanov, Kirill A., Klee, Eric W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667315/
https://www.ncbi.nlm.nih.gov/pubmed/32918542
http://dx.doi.org/10.1002/mgg3.1477
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author Schultz‐Rogers, Laura
Masuho, Ikuo
Pinto e Vairo, Filippo
Schmitz, Christopher T.
Schwab, Tanya L.
Clark, Karl J.
Gunderson, Lauren
Pichurin, Pavel N.
Wierenga, Klaas
Martemyanov, Kirill A.
Klee, Eric W.
author_facet Schultz‐Rogers, Laura
Masuho, Ikuo
Pinto e Vairo, Filippo
Schmitz, Christopher T.
Schwab, Tanya L.
Clark, Karl J.
Gunderson, Lauren
Pichurin, Pavel N.
Wierenga, Klaas
Martemyanov, Kirill A.
Klee, Eric W.
author_sort Schultz‐Rogers, Laura
collection PubMed
description BACKGROUND: GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. METHODS: Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. RESULTS: A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. CONCLUSION: Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans.
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spelling pubmed-76673152020-11-20 Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder Schultz‐Rogers, Laura Masuho, Ikuo Pinto e Vairo, Filippo Schmitz, Christopher T. Schwab, Tanya L. Clark, Karl J. Gunderson, Lauren Pichurin, Pavel N. Wierenga, Klaas Martemyanov, Kirill A. Klee, Eric W. Mol Genet Genomic Med Original Articles BACKGROUND: GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. METHODS: Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. RESULTS: A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. CONCLUSION: Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans. John Wiley and Sons Inc. 2020-09-12 /pmc/articles/PMC7667315/ /pubmed/32918542 http://dx.doi.org/10.1002/mgg3.1477 Text en © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Schultz‐Rogers, Laura
Masuho, Ikuo
Pinto e Vairo, Filippo
Schmitz, Christopher T.
Schwab, Tanya L.
Clark, Karl J.
Gunderson, Lauren
Pichurin, Pavel N.
Wierenga, Klaas
Martemyanov, Kirill A.
Klee, Eric W.
Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title_full Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title_fullStr Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title_full_unstemmed Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title_short Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder
title_sort haploinsufficiency as a disease mechanism in gnb1‐associated neurodevelopmental disorder
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667315/
https://www.ncbi.nlm.nih.gov/pubmed/32918542
http://dx.doi.org/10.1002/mgg3.1477
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