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

Pamela Magini, Tommaso Pippucci, I. Chun Tsai, Simona Coppola, Emilia Stellacci, Anna Bartoletti-Stella, Daniela Turchetti, Claudio Graziano, Giovanna Cenacchi, Iria Neri, Duccio Maria Cordelli, Valentina Marchiani, Rosalba Bergamaschi, Giuseppe Gasparre, Giovanni Neri, Laura Mazzanti, Annalisa Patrizi, Emilio Franzoni, Giovanni Romeo, Domenico BordoMarco Tartaglia, Nicholas Katsanis, Marco Seri

Research output: Contribution to journalArticle


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,weshow 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.

Original languageEnglish
Article numberddu070
Pages (from-to)3607-3617
Number of pages11
JournalHuman Molecular Genetics
Issue number13
Publication statusPublished - 2014


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Magini, P., Pippucci, T., Tsai, I. C., Coppola, S., Stellacci, E., Bartoletti-Stella, A., Turchetti, D., Graziano, C., Cenacchi, G., Neri, I., Cordelli, D. M., Marchiani, V., Bergamaschi, R., Gasparre, G., Neri, G., Mazzanti, L., Patrizi, A., Franzoni, E., Romeo, G., ... Seri, M. (2014). A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype. Human Molecular Genetics, 23(13), 3607-3617. [ddu070]. https://doi.org/10.1093/hmg/ddu070