Elsevier

Brain and Development

Volume 27, Issue 3, April 2005, Pages 211-217
Brain and Development

Original article
Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms

https://doi.org/10.1016/j.braindev.2004.06.003Get rights and content

Abstract

A total of 45 different mutations of methyl-CpG-binding protein 2 gene (MECP2) were identified in 145 of 219 Japanese patients with typical or atypical Rett syndrome (RTT) (66.2%). A missense mutation, T158M was the most common mutation of MECP2, identified in 22 (19.1%) patients, followed by four nonsense mutations, R168X (14.8%), R270X (13.0%), R255X (9.6%), and R294X (6.1%) in 115 patients with classical RTT. Two missense mutations, R133C (33.3%) and R306C (23.3%), and a nonsense mutation, R294X (13.3%), were common in 30 patients with atypical RTT, including the preserved speech variant (PSV). Frameshift mutations due to nucleotide deletion or insertion were identified in 22 patients with MECP2 mutations, and one of them had a 3.6 kb deletion encompassing exons 3 and 4. Three patients with classical RTT had a splicing anomaly. The wide spectrum of phenotypic variability in patients with RTT has been considered to be correlated with the mutation type and location in MECP2, and X-inactivation. However, most patients showed a random X-inactivation pattern evaluated by an androgen receptor gene polymorphism in this study, suggesting that a skewed X-inactivation might not be a main modification factor on clinical phenotypes of RTT. In addition, three new missense mutations, P176R, A378V and T479M, were identified in patients with RTT, but also in healthy Japanese, indicating that these mutations are non-pathogenic in Japanese. Information about rare polymorphic variations is very important for the molecular diagnosis of RTT, although rare polymorphic variants might differ among ethnic groups.

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

References (41)

  • F. Xiang et al.

    Mutation screening in Rett syndrome patients

    J Med Genet

    (2000)
  • K. Obata et al.

    Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in patients with Rett syndrome

    J Med Genet

    (2000)
  • J.P. Cheadle 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)
  • K. Amano et al.

    Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome

    J Hum Genet

    (2000)
  • P. Nicolao et al.

    DBPLC analysis of the MECP2 gene in Italian Rett patients

    Hum Mutat

    (2001)
  • J.B. Nielsen et al.

    MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern

    Eur J Hum Genet

    (2001)
  • T. Bienvenu et al.

    French consortium for MECP2 gene analysis. Spectrum of MECP2 mutations in Rett syndrome

    Genet Test

    (2002)
  • P. Huppke et al.

    Influence of mutation type and location on phenotype in 123 patients with Rett syndrome

    Neuropediatrics

    (2002)
  • C. De Bona et al.

    Preserved speech variant is allelic of classic Rett syndrome

    Eur J Hum Genet

    (2000)
  • M. Zappella et al.

    Preserved speech variants in the Rett syndrome: molecular and clinical analysis

    Am J Med Genet

    (2001)
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