PAK3 MUTATION IN NONSYNDROMIC X-LINKED MENTAL-RETARDATION

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinicall y homogeneous but genetically heterogeneous disorders, whose genetic b ases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonin e kinase. PAK proteins are crucial effecters linking Rho GTPases to cy toskeletal reorganization and to nuclear signalling. The mutation prod uces premature termination, disrupting kinase function. MRI analysis s howed no gross defects in brain development. Immunofluorescence analys is showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Sign al transduction through Rho GTPases and PAK3 may be critical for human cognitive function.