Screening of ARX in mental retardation families: consequences for the strategy of molecular diagnosis
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Mutations in the human ARX gene have been shown to cause nonsyndromic X-linked mental retardation (MRX) as well as syndromic forms such as X-linked lissencephaly with abnormal genitalia (XLAG), Partington syndrome and X-linked infantile spasm. The most common causative mutation, a duplication of 24 bp, was found in families with a variety of phenotypes, but not in the more severe XLAG phenotypes. The aim of the study was to access the frequency of ARX mutations in families with established or putative X-linked mental retardation (XLMR) collected by the European XLMR Consortium. We screened the entire coding region of ARX for mutations in 197 novel XLMR families by denaturing high-performance liquid chromatography, and we identified eight mutations (six c.428_451dup24, one insertion and one novel missense mutation p.P38S). To better define the prevalence of ARX mutations, we included previously reported results of 157 XLMR families. Together, these data showed the relatively high rate (9.5%) of ARX mutations in X-linked MR families and an expectedly low rate in families with affected brother pairs (2.2%). This study confirms that the frequency of ARX mutations is high in XLMR, and the analysis of ARX in MRX should not be limited to duplication.
KeywordsARX mutations Mental retardation ISSX PRTS X-chromosome
We thank patients, family members and the European XLMR Consortium and its members for their participation in this study. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation Electricité de France, The European Community (contract QLG3-CT-2002-01810), Fondation Bettencourt Schuler, Association Française du Syndrome de Rett, Fondation France Telecom and Fondation Jerome Lejeune. K.P. is supported by a Ph.D. fellowship from the French Ministère de la Recherche.
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