A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype.


Journal Article

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 PAK3(N389) 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.

Full Text

Cited Authors

  • Magini, P; Pippucci, T; Tsai, I-C; Coppola, S; Stellacci, E; Bartoletti-Stella, A; Turchetti, D; Graziano, C; Cenacchi, G; Neri, I; Cordelli, DM; Marchiani, V; Bergamaschi, R; Gasparre, G; Neri, G; Mazzanti, L; Patrizi, A; Franzoni, E; Romeo, G; Bordo, D; Tartaglia, M; Katsanis, N; Seri, M

Published Date

  • July 1, 2014

Published In

Volume / Issue

  • 23 / 13

Start / End Page

  • 3607 - 3617

PubMed ID

  • 24556213

Pubmed Central ID

  • 24556213

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddu070


  • eng

Conference Location

  • England