Mutations in GDI1 are responsible for X-linked non-specific mental retardation

Abstract

Rab GDP-dissociation inhibitors (GDI) are evolutionarily conserved proteins that play an essential role in the recycling of Rab GTPases required for vesicular transport through the secretory pathway. We have found mutations in the GDI1 gene (which encodes uGDI) in two families affected with X-linked non-specific mental retardation. One of the mutations caused a non-conservative substitution (L92P) which reduced binding and recycling of RAB3A, the second was a null mutation. Our results show that both functional and developmental alterations in the neuron may account for the severe impairment of learning abilities as a consequence of mutations in GDI1, emphasizing its critical role in development of human intellectual and learning abilities.

A New Functional Domain of Guanine Nucleotide Dissociation Inhibitor (α‐GDI) Involved in Rab Recycling

“…Thus, it may be necessary to localize a-GDI via a Rab3A-independent mechanism to the fusion site to coordinate the rapid events triggering GTP hydrolysis with neurotransmitter release and retrieval of Rab-GDP. The importance of a-GDI at the synapse is underscored by the fact that loss of a-GDI function leads to non-syndromic X-linked mental retardation (XLMR) (28) and, potentially, syndromic-XLMR (29). Our results raise the possibility that a-GDI control of Rab3A levels on synaptic membranes may play a heretofore unappreciated role in regulating synapse function in transmitter release and in neural development.…”

NovelJARID1C/SMCX mutations in patients with X-linked mental retardation

“…In contrast to other NS-XLMR genes in which mutations were found only in single or very few families, e.g. ARGHEF6 [Kutsche et al, 2000], AGTR2 [Vervoort et al, 2002], and GDI1 [D'Adamo et al, 1998], JARID1C appears to be one of the more frequently mutated genes.…”

Genetics and pathophysiology of mental retardation

“…Potential roles in the regulation of synaptic activity have also been proposed for another subgroup of genes involved in MR conditions that encode for transmembrane proteins such as NLGN4, 48,49 DLG3 50 and IL1RAPL 51 and for the soluble protein GDI1. 52,53 At first sight, predicted primary functions of these proteins are diverse and different from those highlighted in the previous paragraph. However, it is interesting to mention, at least for the proteins that have been thoroughly analyzed, that these proteins have in common the subcellular localization at the pre-and/or postsynaptic compartments.…”

“…Mutations identified in DLG3 shown to be associated with MR are predicted to impair the ability of SAP102 to interact with NMDA receptors and/or other proteins involved in downstream NMDA receptor signaling pathways. 50 For the two other XLMR-related genes, GDI1 52,53 and IL1RAPL, 51 literature data are also suggesting their participation in the regulation of synaptic activity. In the mammalian brain, GDIa encoded by the GDI1 gene is the most abundant form of GDI in the CNS and was thought to be involved in the regulation of Rab proteins, which participate in synaptic vesicle recycling and fusion.…”