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

Autor: Kernohan KD; Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada., McBride A; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Hartley T; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Rojas SK; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Dyment DA; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada., Boycott KM; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada., Dyack S; Department of Pediatrics, Dalhousie University and IWK Health Centre, Halifax, Nova Scotia, Canada.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2019 Nov; Vol. 96 (5), pp. 449-455. Date of Electronic Publication: 2019 Aug 13.
DOI: 10.1111/cge.13618
Abstrakt: 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.
(© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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