p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy

Care4Rare Canada Consortium

doi:10.1111/cge.13618

p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy

Care4Rare Canada Consortium

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

16 Citas (Scopus)

Resumen

The p21-activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/β-catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of β-catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.

Idioma original	English
Páginas (desde-hasta)	449-455
Número de páginas	7
Publicación	Clinical Genetics
Volumen	96
N.º	5
DOI	https://doi.org/10.1111/cge.13618
Estado	Published - nov. 1 2019
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
The authors would first and foremost like to thank the study participant and her family. We would also like to acknowledge the contributions of the high throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. The project was selected for analysis by the Care4Rare Consortium Gene Discovery Steering Committee consisting of Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children's Hospital of Eastern Ontario Foundation.

Publisher Copyright:
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

ASJC Scopus Subject Areas

Genetics
Genetics(clinical)

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abstract = "The p21-activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/β-catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of β-catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.",

author = "{Care4Rare Canada Consortium} and Kernohan, {Kristin D.} and Arran McBride and Taila Hartley and Rojas, {Samantha K.} and Dyment, {David A.} and Boycott, {Kym M.} and Sarah Dyack",

note = "Funding Information: The authors would first and foremost like to thank the study participant and her family. We would also like to acknowledge the contributions of the high throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. The project was selected for analysis by the Care4Rare Consortium Gene Discovery Steering Committee consisting of Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa). This work was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children's Hospital of Eastern Ontario Foundation. Publisher Copyright: {\textcopyright} 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",

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AU - Dyment, David A.

AU - Boycott, Kym M.

AU - Dyack, Sarah

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p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

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