Original articleMethyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms
Introduction
Rett syndrome (RTT) (OMIM 312750) is a common cause of mental retardation in females, with a prevalence of 1 in 10,000∼15,000 worldwide [1], [2]. The clinical manifestations in the classical form of RTT are characterized by cognitive deterioration with autistic features, loss of acquired skills such as language and hand usage, stereotypical hand wringing movements, and gait ataxia, appearing after a period of apparently normal development (until 6–18 months) [3]. However, atypical variants of RTT are also commonly observed, and five distinct categories of atypical forms have been delineated on the bases of clinical criteria: infantile seizure onset type, congenital forth, ‘forme fruste’, PVS, and late childhood regression form [4].
Since the first report on mutations in the methyl-CpG binding protein 2 gene (MECP2) in patients with RTT [5], over 200 different mutations of MECP2 have been identified in patients with classical RTT and atypical RTT [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Furthermore, patients with X-linked mental retardation syndrome (XLMR) have different mutations in MECP2 from those in patients with RTT [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. The wide spectrum of phenotypic variability in patients with MECP2 mutations has extensively been discussed and considered with respect to mutation type and location in the gene, in addition to the pattern of X-inactivation [6], [9], [11]. However, some missense mutations reported in patients with RTT and XLMR might be non-pathogenic DNA substitutions such as single nucleotide polymorphisms (SNPs) [16], [17], [38], [39].
To provide further delineation of MECP2 mutations in RTT patients, we have analyzed MECP2 in 219 Japanese patients with classical or atypical RTT. We found 45 pathogenic mutations in 145 patients with RTT (66.2%) and three new SNPs with amino acid substitutions in exon 4 of MECP2. We suggest that rare missese mutations of MECP2 should be carefully distinguished from rare non-pathological variations in order to determine the cause of clinical conditions in patients with RTT or XLMR (Table 1).
Section snippets
Study patients
A total of 219 unrelated Japanese female patients, ranging in age from 2 to 41 years, were evaluated according to the international diagnostic criteria for RTT [3] by Japanese child neurologists and were referred for molecular analysis of MECP2. Classical RTT was diagnosed in 131 patients who had psychomotor regression after a period of normal development (6–12 months), severe mental retardation, deceleration of head growth and loss of language and purposeful hand skills with stereotypical hand
Mutation spectrum of MECP2
Forty-five different mutations in MECP2 were identified in 145 of 219 (66.2%) sporadic female patients with classical or atypical RTT (Table 1, Table 2); missense mutations in 63 (43.4%), nonsense mutations in 57 (39.3%), frameshift mutations due to nucleotide deletion or insertion in 22 (15.2%) and splicing anomalies in three (2.1%). All mutations were not observed in their parents, indicating de novo mutation.
Discussion
To date, 218 different mutations have been reported in a total of more than 2100 patients [26]. In our study, 45 different mutations of MECP2 were identified in 145 of 219 (66.2%) sporadic female patients with classical or atypical RTT, but 74 patients (33.6%) including 16 with classical RTT did not have a MECP2 mutation in the entire coding and flanking regions. MECP2 mutations were found in 115 of 131 patients with classical RTT (87.8%), but in 30 of 88 patients with atypical RTT (34.1%) in
Acknowledgements
We thank all the patients, their parents, and Japanese child neurologists for their interest and support. We also thank Drs Isaku Horiuchi, Akira Kimura, Kenji Mori, and Michiko Sone for their efforts in recruiting families early in this project. We acknowledge the invaluable help of Dr Gray A. in the preparation of the English version of the manuscript. This work was supported by the Fund for ‘Research for the Future’ Program from the Japan Society for the Promotion of Science (JSPS) and the
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2012, Pharmacology and TherapeuticsCitation Excerpt :In 70 to 80% of cases, RTT is caused by mutations in the transcriptional regulator methyl CpG binding protein 2 (MECP2) gene (Huppke & Gartner, 2005); in approximately 80% of individuals with classic RTT and 40% with atypical RTT (Christodoulou & Ho, 1993). In most cases, more than 60% of mutations are caused by missense and nonsense mutations (Laccone et al., 2001; Fukuda et al., 2005; Percy et al., 2007), where nonsense mutation accounts for approximately 35% of classic RTT syndrome cases, with R168X, R270X, R255X, and R294X as the four most common PTC mutations (Fukuda et al., 2005; Percy et al., 2007). RTT is one of the most common causes of mental retardation in females.
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