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- Title
A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype.
- Authors
Magini, Pamela; Pippucci, Tommaso; Tsai, I-Chun; Coppola, Simona; Stellacci, Emilia; Bartoletti-Stella, Anna; Turchetti, Daniela; Graziano, Claudio; Cenacchi, Giovanna; Neri, Iria; Cordelli, Duccio Maria; Marchiani, Valentina; Bergamaschi, Rosalba; Gasparre, Giuseppe; Neri, Giovanni; Mazzanti, Laura; Patrizi, Annalisa; Franzoni, Emilio; Romeo, Giovanni; Bordo, Domenico
- Abstract
Loss–of-function mutations in PAK3 contribute to non-syndromic X-linked intellectual disability (NS-XLID) by affecting dendritic spine density and morphology. Linkage analysis in a three-generation family with affected males showing ID, agenesis of corpus callosum, cerebellar hypoplasia, microcephaly and ichthyosis, revealed a candidate disease locus in Xq21.33q24 encompassing over 280 genes. Subsequent to sequencing all coding exons of the X chromosome, we identified a single novel variant within the linkage region, affecting a conserved codon of PAK3. Biochemical studies showed that, similar to previous NS-XLID-associated lesions, the predicted amino acid substitution (Lys389Asn) abolished the kinase activity of PAK3. In addition, the introduced residue conferred a dominant-negative function to the protein that drives the syndromic phenotype. Using a combination of in vitro and in vivo studies in zebrafish embryos, we show that PAK3N389 escapes its physiologic degradation and is able to perturb MAPK signaling via an uncontrolled kinase-independent function, which in turn leads to alterations of cerebral and craniofacial structures in vivo. Our data expand the spectrum of phenotypes associated with PAK3 mutations, characterize a novel mechanism resulting in a dual molecular effect of the same mutation with a complex PAK3 functional deregulation and provide evidence for a direct functional impact of aberrant PAK3 function on MAPK signaling.
- Publication
Human Molecular Genetics, 2014, Vol 23, Issue 13, p3607
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu070