Abstract
A high frequency of mutations in the methyl CpG-binding protein 2 (MECP2) gene has recently been reported in males with nonspecific X-linked mental retardation. The results of this previous study suggested that the frequency of MECP2 mutations in the mentally retarded population was comparable to that of CGG expansions in FMR1. In view of these data, we performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for FMR1 CGG repeat expansion. Five novel changes, detected in seven patients, were predicted to change the MECP2 coding sequence. Except for one, these changes were not found in a control population. While this result appeared to suggest a high mutation rate, this conclusion was not supported by segregation studies. Indeed, three of the five changes could be traced in unaffected male family members. For another change, segregation analysis in the family was not possible. Only one mutation, a frameshift created by a deletion of two bases, was found to be de novo. This study clearly shows the importance of segregation analysis for low frequency mutations, in order to distinguish them from rare polymorphisms. The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475).
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Hagberg B, Goutieres F, Hanefeld F, Rett A, Wilson J . Rett syndrome: criteria for inclusion and exclusion Brain Dev 1985 7: 372–373
Clayton-Smith J, Watson P, Ramsden S, Black GCM . Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males Lancet 2000 356: 830–832
Topçu M, Akyerli C, Sayi A et al. Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy Eur J Hum Genet 2002 10: 77–81
Villard L, Kpebe A, Cardoso C, Chelly J, Tardieu M, Fontes M . Two affected boys in a Rett syndrome family: clinical and molecular findings Neurology 2000 55: 1188–1193
Meloni I, Bruttini M, Longo I et al. A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males Am J Hum Genet 2000 67: 982–985
Hoffbuhr K, Devaney JM, LaFleur B et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome Neurology 2001 56: 1486–1495
Imessaoudene B, Bonnefont JP, Royer G et al. MECP2 mutation in non-fatal, non-progressive encephalopathy in a male J Med Genet 2001 38: 171–174
Watson P, Black G, Ramsden S et al. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein J Med Genet 2001 38: 224–228
Orrico A, Lam CW, Galli L et al. MECP2 mutation in male patients with non-specific X-linked mental retardation FEBS Lett 2000 481: 285–288
Couvert P, Bienvenu T, Aquaviva C et al. MECP2 is highly mutated in X-linked mental retardation Hum Mol Genet 2001 10: 941–946
Yntema HG, Oudakker AR, Kleefstra T et al. In frame deletion in MECP2 causes mild nonspecific mental retardation Am J Med Genet 2002 107: 81–83
de Vries BBA, van den Ouweland AMW, Mohkamsing S et al. Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey Am J Hum Genet 1997 61: 660–667
Kleefstra T, Yntema HG, Oudakker AR et al. De novo MECP2 frameshift mutation in a moderately retarded boy Clin Genet, 2002 61: 359–362
Glatt CE, DeYoung JA, Delgado S et al. Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes Nat Genet 2001 27: 435–438
Jeanpierre M . Pathogenic mutation or low-frequency polymorphism? Frequency of a DNA variant not found in n chromosomes is less than 3 divided by n (In French) Ann Genet 1996 39: 133–138
Moncla A, Kpebe A, Missirian C, Mancini J, Villard L . Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped boys: implications for genetic counselling Eur J Hum Genet 2002 10: 86–89
Cheadle JP, Gill H, Fleming N et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location Hum Mol Genet 2000 9: 1119–1129
Wan M, Lee SSJ, Zhang X et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots Am J Hum Genet 1999 65: 1520–1529
Acknowledgements
We would like to thank Gerly van der Vleuten for statistical analysis. This research was supported by ZorgOnderzoek Nederland (ZON), project 2100-0041.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yntema, H., Kleefstra, T., Oudakker, A. et al. Low frequency of MECP2 mutations in mentally retarded males. Eur J Hum Genet 10, 487–490 (2002). https://doi.org/10.1038/sj.ejhg.5200836
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200836
Keywords
This article is cited by
-
MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype–phenotype correlations and validation of high-resolution melting analysis for mutation scanning
Journal of Human Genetics (2016)
-
Rett syndrome: new clinical and molecular insights
European Journal of Human Genetics (2006)
-
Mechanisms of Disease: neurogenetics of MeCP2 deficiency
Nature Clinical Practice Neurology (2006)
-
Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized
Nature Reviews Genetics (2006)
-
Macrocephalic mental retardation associated with a novel C-terminal MECP2 frameshift deletion
European Journal of Pediatrics (2005)
