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

A Correction to this article was published on 01 July 1998

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 αGDI) 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.

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Figure 1: Mutations in patients MRX41 and MRX48.
Figure 2: Western-blot analysis of αGDI in a normal individual and MRX patients.
Figure 3: Effect of the L92P mutation on RAB3A binding and recycling.
Figure 4: Gdi1 expression during mouse brain development.
Figure 5: Inhibition of axonal outgrowth of hippocampal neurons treated with Gdi1 antisense oligonucleotides.

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Acknowledgements

We thank P. Willems and A. Meindl for the DNA of patients MRX25 and MRX28, M. Zerial for the gift of the anti-αGDI antibodies, D. Dunlop for help with the computer program, E. Boncinelli for the hospitality to do in situ hybridizations; M. Gatti for skillful technical assistance, K. Zeng for preparation of the illustrations showing structural changes in αGDI and the Galliera Genetic Bank (program C23) for the patient samples. This work was funded by Telethon Italy (D.T. and F.V.) and by GM33301 and EY11606 (W.E.B.).

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Correspondence to Daniela Toniolo.

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D'Adamo, P., Menegon, A., Lo Nigro, C. et al. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet 19, 134–139 (1998). https://doi.org/10.1038/487

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