PUBLICATION
A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype
- Authors
- 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.
- ID
- ZDB-PUB-140513-498
- 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.
Citation
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. (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):3607-17.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping