The Scientist - September 14th, 1998
Notebook: Good Thinking
By multiple authors
From a research point of view, the problem with most genetic causes of
mental retardation is that a number of genes are involved, affecting several
organs, and therefore providing little new insight into how the brain works.
But recent discoveries concerning mutations that cause nonsyndromic X-linked
mental retardation (MRX), show promise of helping to explain normal
cognitive functions. MRX affects 1 in 600 males, whose brain development
generally seems otherwise normal, and who exhibit few or no other signs of
retardation. However, MRX syndromes are genetically diverse, comprising more
than 60 pedigrees. Genes for several pedigrees have been located on the X
chromosome, the latest identified by a multi-institution research group that
found a defect in the PAK3 (p21-activated kinase) gene for the MRX30
pedigree (K.M. Allen et al., Nature Genetics, 20:25-30, Sept. 1998).
"Because the protein is brain-specific and clearly has a brain phenotype, we
can isolate its functions," explains lead author Kristina M. Allen, a
Harvard Medical School researcher at Beth Israel Deaconess Medical Center.
PAK3 appears to be involved in both signal transduction and in regulating
neuronal cell shape. In particular, it may affect axonal and dendritic
development. Although the group has been working with cell lines, the amino
acid sequence of PAK proteins is highly conserved. "Our next step is to look
at the effects [of PAK3] on neuronal growth and development in cells," Allen
says, after which the mutation can be introduced into mice, to see what role
it plays in relation to other known mental retardation genes.