[PDF][PDF] Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the …
AM Lossi, JM Millan, L Villard, C Orellana… - The American Journal of …, 1999 - cell.com
The American Journal of Human Genetics, 1999•cell.com
The gene involved in the ATR-X syndrome was isolated in 1994 (by Gecz et al.) and named
“XNP.” It has since been shown to be mutated in 13 patients with alpha-thalassemia MR
(ATR-X) syndrome (Gibbons et al. 1995b). Moreover, mutations in this gene have also been
identified in families affected with Juberg-Marsidi syndrome (MIM 309590) and with MR
syndromes without alpha-thalassemia (Villard et al. 1996a, 1996b, 1996c). More recently, a
new mutation has been found, in Carpenter-Waziri syndrome (Abidi et al. 1999). The gene is …
“XNP.” It has since been shown to be mutated in 13 patients with alpha-thalassemia MR
(ATR-X) syndrome (Gibbons et al. 1995b). Moreover, mutations in this gene have also been
identified in families affected with Juberg-Marsidi syndrome (MIM 309590) and with MR
syndromes without alpha-thalassemia (Villard et al. 1996a, 1996b, 1996c). More recently, a
new mutation has been found, in Carpenter-Waziri syndrome (Abidi et al. 1999). The gene is …
The gene involved in the ATR-X syndrome was isolated in 1994 (by Gecz et al.) and named “XNP.” It has since been shown to be mutated in 13 patients with alpha-thalassemia MR (ATR-X) syndrome (Gibbons et al. 1995b). Moreover, mutations in this gene have also been identified in families affected with Juberg-Marsidi syndrome (MIM 309590) and with MR syndromes without alpha-thalassemia (Villard et al. 1996a, 1996b, 1996c). More recently, a new mutation has been found, in Carpenter-Waziri syndrome (Abidi et al. 1999). The gene is large (probably extending over 300 kb) and consists of 35 exons. It encodes a putative zinc-finger helicase (Villard et al. 1997) that is probably involved, by remodeling the structure of the chromatin, in the control of gene expression. This assumption is supported by the finding of an interaction between the XNP protein and the Ezh2 protein (Cardoso et al. 1998), the human equivalent of Drosophila enhancer of zeste, a chromatinian protein of the Polycomb group. To date, 34 different mutations in 50 pedigrees have been described in the XNP/ATR-X gene, which are located either in the region coding for the three zinc-finger domains of the protein (exons 7 and 8 and the beginning of exon 9) or in the helicase domain, which extends over 3 kb at the COOH terminus of the putative protein. We thus decided to search for mutations in this gene in a patient from the MRSP family. This was performed by systematic sequencing of the gene. We found one mutation in the gene, changing an arginine from the conserved helicase domain III into a lysine, R1742K (fig. 2). This mutation perfectly segregates with the disorder in the family (fig. 3). Moreover, the mutation was absent from 100 unrelated chromosomes from the same geographical area as that of the family we studied. We performed reverse-transcription PCR (RT-PCR) on RNA from lymphocytes of the patients, to check for any putative effect of the mutation on the mRNA splicing, which has been previously reported to occur in this gene (Villard et al. 1996b) but we failed to find any abnormalsize product (data not shown). Since this amino acid change (arginine to lysine) is generally considered to be conservative, we used a local structure–prediction program (PEPTIDESTRUCTURE, from the GCG package, which mainly predicts a helices
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