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Human Molecular Genetics, 2001, Vol. 10, No. 9 941-946
© 2001 Oxford University Press

MECP2 is highly mutated in X-linked mental retardation

Philippe Couvert1, Thierry Bienvenu1,2, Cecile Aquaviva2, Karine Poirier1, Claude Moraine3, Chantal Gendrot3, Alain Verloes4, Christian Andrès3, Anne Celine Le Fevre2, Isabelle Souville2, Julie Steffann2, Vincent des Portes1, Hans-Hilger Ropers5, Helger G. Yntema6, Jean-Pierre Fryns7, Sylvain Briault3, Jamel Chelly1,+ and Beldjord Cherif1,2

1INSERM Unité 129-ICGM, CHU Cochin 24 Rue du Faubourg Saint Jacques, 75014 Paris, France, 2Laboratoire de Biochimie et Génétique Moléculaire, CHU Cochin, Paris, France, 3CHU de Tours, Service de Génétique, Hopital Bretonneau, 37044 Tours Cedex, France, 4Centre Universitaire Wallon de Génétique, CUWG CHU Sart Tilman Domaine Universitaire, Liège B-4000, Belgium, 5Max-Plank-Institute for Molecular Genetics, Ihnestrasse 73, Berlin-Dahlem, Germany, 6University Hospital Nijmegen, 417 Department of Human Genetics, 6500 HB Nijmegen, The Netherlands and 7Center for Human Genetics, Clinical Genetics University, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.

+ To whom correspondence should be addressed. Tel: +33 1 44 41 24 10; Fax: +33 1 44 41 24 21; Email: chelly@icgm.cochin.inserm.fr


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