Nonsyndromal mental retardation

The genetic basis of four non-syndromal XLMR conditions has been identified and, remarkably, three of the four genes are related. They are GDI1, oligophrenin, and PAK3/36,37 and38,) GDI1 is a guanine diphosphate (GDP) dissociation inhibitor of the protein Rab3a, a small guanosine triphosphate ( GTP) binding protein that plays a role in the recruitment of synaptic vesicles for exocytosis.(39) Oligophrenin encodes a rhoGAP protein that stimulates the intrinsic GTPase activity of small G proteins. PAK3 links Rac and Cdc42 to the actin cytoskeleton nd to transcriptional activation. Thus GDI1, oligophrenin, and PAK3 are all involved in Rho GTPase signalling networks. What does this tell us about the pathogenesis of mental retardation?

At present, there are two possibilities. The first is that normal development of axonal connections is disrupted in patients with mutations in these genes. As yet that hypothesis is unproved, but it fits with what is known about the cell biology of the Rho GTPases. (49 Axons and neurites find their way through the developing brain by sampling molecular signals, helped by GTPases, and dendritic formation (like other cellular extensions, filopodia, and lamellae) is reduced by inhibiting Rho GTPases. Furthermore, the pattern of GDI1 expression in the developing brain is consistent with a developmental role. (37) The second possibility is that synaptic function is compromised. The main evidence here comes from our understanding of the function of Rab3a, a protein that is only expressed in neurones and neuroendocrine cells and localizes to secretory vesicles. A decrease in intracellular Rab3a concentrations, due to the GDI1 mutation, could reduce neurotransmitter release.

The fourth gene implicated in non-syndromal mental retardation is FMR2.(4,42> We know next to nothing about what the gene does, other than that it encodes a nuclear protein that may regulate transcription.(4 d4' The dearth of information about its function is more typical of our knowledge of genes involved in mental retardation than is suggested by the success with Rho GTPase family of genes.

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