Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder.
Am J Hum Genet
; 103(4): 579-591, 2018 10 04.
Article
em En
| MEDLINE
| ID: mdl-30290153
ABSTRACT
p21-activated kinases (PAKs) are serine/threonine protein kinases acting as effectors of CDC42 and RAC, which are members of the RHO family of small GTPases. PAK1's kinase activity is autoinhibited by homodimerization, whereas CDC42 or RAC1 binding causes PAK1 activation by dimer dissociation. Major functions of the PAKs include actin cytoskeleton reorganization, for example regulation of the cellular protruding activity during cell spreading. We report the de novo PAK1 mutations c.392A>G (p.Tyr131Cys) and c.1286A>G (p.Tyr429Cys) in two unrelated subjects with developmental delay, secondary macrocephaly, seizures, and ataxic gait. We identified enhanced phosphorylation of the PAK1 targets JNK and AKT in fibroblasts of one subject and of c-JUN in those of both subjects compared with control subjects. In fibroblasts of the two affected individuals, we observed a trend toward enhanced PAK1 kinase activity. By using co-immunoprecipitation and size-exclusion chromatography, we observed a significantly reduced dimerization for both PAK1 mutants compared with wild-type PAK1. These data demonstrate that the two PAK1 variants function as activating alleles. In a cell spreading assay, subject-derived fibroblasts showed significant enrichment in cells occupied by filopodia. Interestingly, application of the PAK1 inhibitor FRAX486 completely reversed this cellular phenotype. Together, our data reveal that dominantly acting, gain-of-function PAK1 mutations cause a neurodevelopmental phenotype with increased head circumference, possibly by a combined effect of defective homodimerization and enhanced kinase activity of PAK1. This condition, along with the developmental disorders associated with RAC1 and CDC42 missense mutations, highlight the importance of RHO GTPase members and effectors in neuronal development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinases Ativadas por p21
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Transtornos do Neurodesenvolvimento
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Mutação com Ganho de Função
Tipo de estudo:
Observational_studies
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Risk_factors_studies
Limite:
Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Alemanha