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,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 language | English (US) |
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Article number | ddu070 |
Pages (from-to) | 3607-3617 |
Number of pages | 11 |
Journal | Human molecular genetics |
Volume | 23 |
Issue number | 13 |
DOIs | |
State | Published - Jul 2014 |
Funding
Medical and family history, with particular regard to neurological and cutaneous involvement, was obtained. Physical examination of the proband III-2 and of his cousin III-4 included assessment of height, weight and dysmorphic features. The neurological examination was especially focused on the evaluation of the electric activity of the brain by EEG and on the detection of cerebral malformations by MRI. The dermatological evaluation was supported by skin biopsy and was extended to carrier females. After abortion, the fetus III-5 was subjected to autopsy to confirm the brain anomaly previously detected by ultrasound scan and to reveal possible skin alterations.
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)