MECP2 mutation screening in Swedish classical Rett syndrome females

Rett syndrome (RS) is a neurodevelopmental disorder almost exclusively affe cting females. We have studied the mutation spectrum of the responsible gen e MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), in 16 sporadic clas sical RS females from Sweden. In 13 of 16 patients (81%) we detected nonsen se or missense mutations in the coding parts of MECP2. This mutation rate i s in agreement with other reports (65-80%). In all, 12 different mutations and one polymorphism were found; three of the mutations have not been repor ted previously. The missense mutations were restricted to highly conserved regions of the gene. None of the mutations was detected in parents; thus, t hey had probably arisen de novo. In contrast, two normal variants, one intr on deletion and one silent mutation, were seen singly only in two patients' mothers; neither has been reported previously. One patient showed two diff erent mutations closely located, i.e. 802C > T (R268W) together with 808C > T (R270X). Another patient had a mutation in the stop codon 1459T > C (X48 7R), leading to a gene product prolonged with 27 amino acids. In conclusion , our results indicate that the majority of Swedish RS patients (81%) have mutations in MECP2 that are sporadic cases with de novo mutations. Moreover , both missense and nonsense mutations occur, but in different parts of the gene, probably reflecting the function of the domains in MeCP2. This study has improved our ability to offer these families an early confirmation of Rett diagnoses.