Abstracts
Résumé
Les retards mentaux liés au chromosome X (RMLX), qui touchent 1,8 garçons pour 1 000 naissances masculines, sont classiquement divisés en formes syndromiques et formes non spécifiques, selon la présence ou non de signes particuliers associés au retard mental. L’extrême hétérogénéité phénotypique et allélique, parfois visible au sein d’une même famille, complique toutefois cette classification. L’évaluation rétrospective appronfondie des familles atteintes, une fois la mutation identifiée dans un gène, devrait aider à clarifier la situation et faciliter la prise en charge du diagnostic moléculaire de ces retards mentaux. L’analyse des protéines produites par les 60 gènes de RMLX actuellement identifiés montre une grande diversité des fonctions biologiques affectées dans le retard mental. Dans cette revue, nous présenterons les données récentes concernant trois gènes, FMR1, ARX et le gène de l’oligophrénine 1, qui non seulement illustrent la complexité des RMLX, mais soulignent aussi l’importance des voies de signalisation impliquées dans la régulation de l’expression génique, ainsi que celles relayées pas les GTPases Rho dans la maturation et la plasticité neuronale.
Summary
X-linked mental retardation (XLMR) affects 1.8 ‰ male births and is usually categorized as “syndromic” (MRXS) or “non-specific” (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes.
Appendices
Références
- 1. Ropers HH, Hamel BC. X-linked mental retardation. Nat Rev Genet 2005 ; 6 : 46-57.
- 2. Hagerman RJ, Silverman AC. Fragile X syndrome : diagnosis, treatment, and research. Baltimore : Johns Hopkins University Press, 1991 ; XIV : 378 p.
- 3. Fisch GS, Simensen R, Tarleton J, et al. Longitudinal study of cognitive abilities and adaptive behavior levels in fragile X males : a prospective multicenter analysis. Am J Med Genet 1996 ; 64 : 356-61.
- 4. Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 2000 ; 10 : 1038-44.
- 5. Hagerman PJ, Hagerman RJ. The fragile-X premutation : a maturing perspective. Am J Hum Genet 2004 ; 74 : 805-16.
- 6. Bardoni B, Mandel JL. Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr Opin Genet Dev 2002 ; 12 : 284-93.
- 7. Zalfa F, Giorgi M, Primerano B, et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 2003 ; 112 : 317-27.
- 8. Ishizuka A, Siomi MC, Siomi H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev 2002 ; 16 : 2497-508.
- 9. Schenck A, Bardoni B, Langmann C, et al. CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 2003 ; 38 : 887-98.
- 10. Billuart P, Chelly J. From fragile X mental retardation protein to Rac1 GTPase : new insights from Fly CYFIP. Neuron 2003 ; 38 : 843-5.
- 11. Bienvenu T, Poirier K, Friocourt G, et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002 ; 11 : 981-91.
- 12. Poirier K, Van Esch H, Friocourt G, et al. Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. Brain Res Mol Brain Res 2004 ; 122 : 35-46.
- 13. Nasrallah IM, Minarcik JC, Golden JA. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. J Cell Biol 2004 ; 167 : 411-6.
- 14. Stromme P, Mangelsdorf ME, Scheffer IE, Gecz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev 2002 ; 24 : 266-8.
- 15. Kitamura K, Yanazawa M, Sugiyama N, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002 ; 32 : 359-69.
- 16. Mandel JL, Chelly J. Monogenic X-linked mental retardation : is it as frequent as currently estimated ? The paradox of the ARX (Aristaless X) mutations. Eur J Hum Genet 2004 ; 12 : 689-93.
- 17. Billuart P, Bienvenu T, Ronce N, et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 1998 ; 392 : 923-6.
- 18. Bergmann C, Zerres K, Senderek J, et al. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 2003 ; 126 : 1537-44.
- 19. Philip N, Chabrol B, Lossi AM, et al. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J Med Genet 2003 ; 40 : 441-6.
- 20. Des Portes V, Boddaert N, Sacco S, et al. Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene. Am J Med Genet 2004 ; 124A : 364-71.
- 21. Zanni G, Saillour Y, Nagara M, et al. OPHN1 mutations are a frequent cause of X-linked mental retardation with cerebellar hypoplasia. Neurology 2005 (sous presse).
- 22. Mostofsky SH, Mazzocco MM, Aakalu G, et al. Decreased cerebellar posterior vermis size in fragile X syndrome : correlation with neurocognitive performance. Neurology 1998 ; 50 : 121-30.
- 23. Kaufmann WE, Cooper KL, Mostofsky SH, et al. Specificity of cerebellar vermian abnormalities in autism : a quantitative magnetic resonance imaging study. J Child Neurol 2003 ; 18 : 463-70.
- 24. Govek EE, Newey SE, Akerman CJ, et al. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat Neurosci 2004 ; 7 : 364-72.
- 25. Luo L. Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci 2000 ; 1 : 173-80.
- 26. Renieri A, Pescucci C, Longo I, et al. Non-syndromic X-linked mental retardation : from a molecular to a clinical point of view. J Cell Physiol 2005 ; 240 : 8-20.