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Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). METHOD...

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Autores principales: Marbach, Felix, Stoyanov, Georgi, Erger, Florian, Stratakis, Constantine A., Settas, Nikolaos, London, Edra, Rosenfeld, Jill A., Torti, Erin, Haldeman-Englert, Chad, Sklirou, Evgenia, Kessler, Elena, Ceulemans, Sophia, Nelson, Stanley F., Martinez-Agosto, Julian A., Palmer, Christina G. S., Signer, Rebecca H., Andrews, Marisa V., Grange, Dorothy K., Willaert, Rebecca, Person, Richard, Telegrafi, Aida, Sievers, Aaron, Laugsch, Magdalena, Theiß, Susanne, Cheng, YuZhu, Lichtarge, Olivier, Katsonis, Panagiotis, Stocco, Amber, Schaaf, Christian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354857/
https://www.ncbi.nlm.nih.gov/pubmed/33833410
http://dx.doi.org/10.1038/s41436-021-01152-7
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author Marbach, Felix
Stoyanov, Georgi
Erger, Florian
Stratakis, Constantine A.
Settas, Nikolaos
London, Edra
Rosenfeld, Jill A.
Torti, Erin
Haldeman-Englert, Chad
Sklirou, Evgenia
Kessler, Elena
Ceulemans, Sophia
Nelson, Stanley F.
Martinez-Agosto, Julian A.
Palmer, Christina G. S.
Signer, Rebecca H.
Andrews, Marisa V.
Grange, Dorothy K.
Willaert, Rebecca
Person, Richard
Telegrafi, Aida
Sievers, Aaron
Laugsch, Magdalena
Theiß, Susanne
Cheng, YuZhu
Lichtarge, Olivier
Katsonis, Panagiotis
Stocco, Amber
Schaaf, Christian P.
author_facet Marbach, Felix
Stoyanov, Georgi
Erger, Florian
Stratakis, Constantine A.
Settas, Nikolaos
London, Edra
Rosenfeld, Jill A.
Torti, Erin
Haldeman-Englert, Chad
Sklirou, Evgenia
Kessler, Elena
Ceulemans, Sophia
Nelson, Stanley F.
Martinez-Agosto, Julian A.
Palmer, Christina G. S.
Signer, Rebecca H.
Andrews, Marisa V.
Grange, Dorothy K.
Willaert, Rebecca
Person, Richard
Telegrafi, Aida
Sievers, Aaron
Laugsch, Magdalena
Theiß, Susanne
Cheng, YuZhu
Lichtarge, Olivier
Katsonis, Panagiotis
Stocco, Amber
Schaaf, Christian P.
author_sort Marbach, Felix
collection PubMed
description PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
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spelling pubmed-83548572021-08-14 Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain Marbach, Felix Stoyanov, Georgi Erger, Florian Stratakis, Constantine A. Settas, Nikolaos London, Edra Rosenfeld, Jill A. Torti, Erin Haldeman-Englert, Chad Sklirou, Evgenia Kessler, Elena Ceulemans, Sophia Nelson, Stanley F. Martinez-Agosto, Julian A. Palmer, Christina G. S. Signer, Rebecca H. Andrews, Marisa V. Grange, Dorothy K. Willaert, Rebecca Person, Richard Telegrafi, Aida Sievers, Aaron Laugsch, Magdalena Theiß, Susanne Cheng, YuZhu Lichtarge, Olivier Katsonis, Panagiotis Stocco, Amber Schaaf, Christian P. Genet Med Article PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder. Nature Publishing Group US 2021-04-08 2021 /pmc/articles/PMC8354857/ /pubmed/33833410 http://dx.doi.org/10.1038/s41436-021-01152-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Marbach, Felix
Stoyanov, Georgi
Erger, Florian
Stratakis, Constantine A.
Settas, Nikolaos
London, Edra
Rosenfeld, Jill A.
Torti, Erin
Haldeman-Englert, Chad
Sklirou, Evgenia
Kessler, Elena
Ceulemans, Sophia
Nelson, Stanley F.
Martinez-Agosto, Julian A.
Palmer, Christina G. S.
Signer, Rebecca H.
Andrews, Marisa V.
Grange, Dorothy K.
Willaert, Rebecca
Person, Richard
Telegrafi, Aida
Sievers, Aaron
Laugsch, Magdalena
Theiß, Susanne
Cheng, YuZhu
Lichtarge, Olivier
Katsonis, Panagiotis
Stocco, Amber
Schaaf, Christian P.
Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title_full Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title_fullStr Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title_full_unstemmed Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title_short Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
title_sort variants in prkar1b cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354857/
https://www.ncbi.nlm.nih.gov/pubmed/33833410
http://dx.doi.org/10.1038/s41436-021-01152-7
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