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

作者：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; Tartaglia Marco; Katsanis Nicholas; Seri Marco^*

来源：Human Molecular Genetics, 2014, 23(13): 3607-3617.

DOI：10.1093/hmg/ddu070

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.

• 出版日期2014-7