ZFIN ID: ZDB-PUB-140513-498
A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype
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., Bordo, D., Tartaglia, M., Katsanis, N., Seri, M.
Date: 2014
Source: Human molecular genetics   23(13): 3607-17 (Journal)
Registered Authors: Katsanis, Nicholas, Tsai, I-Chun
Keywords: none
MeSH Terms:
  • Animals
  • Exons/genetics
  • Humans
  • Karyotyping
  • Mitogen-Activated Protein Kinases/genetics
  • Mitogen-Activated Protein Kinases/metabolism*
  • Mutation
  • Signal Transduction/genetics
  • Signal Transduction/physiology
  • p21-Activated Kinases/genetics*
  • ras Proteins/genetics
  • ras Proteins/metabolism*
PubMed: 24556213 Full text @ Hum. Mol. Genet.
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.