Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation

X-linked mental retardation is a very common condition that affects approxi mately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using t he candidate gene approach demonstrated the presence of mutations in PAK3 ( p21-activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been impl icated as critical downstream effecters that link Rho-GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c-dun amino-terminal kinase (JNK) and p38, We screened 12 MRX pedigrees that map to a large reg ion overlying Xq21-q24, Mutation screening of the whole coding region of th e PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involve ment of PAK3 in MRX following the report of a nonsense mutation recently re ported in MRX30, In the MRX47 family, all affected males show moderate to s evere mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R6 7C is located in a conserved polybasic domain (AA 66-68) of the protein tha t is predicted to play a major role in the GTPases binding and stimulation of Pak activity. (C) 2000 Wiley-Liss, Inc.