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Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation
  1. S Kudo1,
  2. Y Nomura2,
  3. M Segawa2,
  4. N Fujita3,
  5. M Nakao3,
  6. S Hammer4,
  7. C Schanen4,
  8. I Terai1,
  9. M Tamura1
  1. 1Hokkaido Institute of Public Health, Sapporo 060-0819, Japan
  2. 2Segawa Neurological Clinic for Children, Tokyo 101-0062, Japan
  3. 3Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan
  4. 4Departments of Human Genetics and Pediatrics and the Mental Retardation Research Center, School of Medicine, University of California at Los Angeles, CA90095-7088, USA
  1. Correspondence to:
 Dr S Kudo, Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan;
 kudos{at}iph.pref.hokkaido.jp

https://doi.org/10.1136/jmg.39.2.132

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    Rett syndrome1 is a neurodevelopmental disorder that primarily affects females and is characterised by a period of normal growth and development, followed by severe neurological dysfunction including dementia, autistic features, loss of purposeful use of the hands, jerky truncal ataxia, and seizures.2 Systematic genetic analyses have shown that mutations in the methyl-CpG binding protein gene MeCP23 are associated with Rett syndrome.4 Recently, MeCP2 mutations (A140V5,6 and E137G6) were also found in male patients with non-specific X linked mental retardation that is clinically distinct from Rett syndrome. To elucidate the functional significance of these mutations, we used transient expression assays to compare the effects of these mutations on MeCP2 function with those of Rett syndrome mutations.4 Wild type and mutant MeCP2/GFP fusion proteins expressed in mouse L929 cells were analysed to determine the effect of mutations on accumulation of MeCP2 in heterochromatin, where approximately half of the methyl-CpG dinucleotides occurring in the genome are located.7 In contrast to an R106W Rett syndrome mutant protein, which has no affinity to heterochromatin, both A140V and E137G mutants showed a clear focal heterochromatin staining pattern indistinguishable from the wild type protein. The effects of mutations on transcriptional repressive activities were also evaluated in Drosophila SL2 cells, which possess only marginal background activities of methyl-CpG binding proteins.8–10 Although R106W expression substantially reduced transcriptional repressive activity, the A140V and the E137G mutants retained the transcriptional repressive activity. In particular, the A140V mutant retained such repressive activity at a level comparable to the wild type protein. These results indicate that potential alterations in MeCP2 function resulting from the A140V and the E137G mutations are different from those associated with mutations observed in Rett syndrome and may explain why the manifestation of MeCP2 related mental disorder in …

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