Human Molecular Genetics, 2000, Vol. 9, No. 9 1377-1384
© 2000 Oxford University Press
MECP2 mutations account for most cases of typical forms of Rett syndrome
Laboratoire de Génétique et Physiopathologie des retards mentaux—ICGM, Faculté de Médecine Cochin, 24 rue du Faubourg Saint Jacques, 75014 Paris, France, 1Laboratoire d’Hormonologie et de Biologie Moléculaire, CHU Bicêtre, 78 rue du général Leclerc, 94275 Le Kremlin Bicêtre, France, 2Laboratoire de Génétique, Hôpitaux de Brabois, rue du Morvan, 54511 Vandoeuvre Les Nancy, France, 3INSERM U406, Faculté de la Timone, 27 boulevard Jean Moulin, 13358 Marseille Cedex, France, 4Service de Neurologie Pédiatrique, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France and 5Département de Pédiatrie, Service de Neurologie, CHU Bicêtre, 78 rue du général Leclerc, 94275 Le Kremlin Bicêtre, France
Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females, with an estimated prevalence of approximately one in 10 000–15 000 female births. Most cases are sporadic, but several reports about familial recurrence support X-linked dominant inheritance with male lethality. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in <25% of RTT cases in this first report. To characterize the spectrum of mutations in the MECP2 gene in RTT patients, we selected 46 typical RTT patients and performed mutation screening by denaturing gradient gel electrophoresis combined with direct sequencing. We identified 30 mutations, accounting for 65% of RTT patients. They include 12 novel mutations (11 located in exon 3 and one in exon 2). Mutations, such as R270X and frameshift deletions in a (CCACC)n rich region, have been found with multiple recurrences. Most of the mutations were de novo, except in one family where the non-affected transmitter mother exhibited a bias of X inactivation. Although this study showed that MECP2 mutations account for most cases of typical forms of RTT (65%) and mutations in non-coding regions cannot be excluded for the remaining cases, an alternative hypothesis that takes into account the homogeneous phenotype and exclusive involvement of females, could be the implication in RTT of a putative second X-linked gene.
+ 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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