Mutation Analysis of the MECP2 Gene in Patients with Rett Syndrome and Rett-like Features
Date Issued
2009
Date
2009
Author(s)
Tsai, Wen-Hsin
Abstract
Background: Mutations in the methy-CpG-binding protein 2 (MECP2) gene are well known to cause Rett syndrome (RTT), a severe neurodevelopmental disorder, occurs almost exclusively in females, with an estimated prevalence of approximately 1 in 10,000-15,000 females. RTT is often considered an X-linked dominant condition with male lethality (Hagberg 1985) characterized by a progressive loss of intellectual function, fine gross motor skills, and communicative abilities; deceleration of head growth; and the development of stereotypic hand movements, all occurring after a period of normal development. To date, mutations have been identified in the MECP2 sequences of approximately 80-90% of all RTT; the remaining 10-20% may possess noncoding regions of this gene, or they may harbor a second RTT inducing gene or locus. Several reports have identified large gene deletions in RTT patients that escaped detection by PCR-based screening strategies (Laccone et al. 2004; Schollen et al. 2003). his study reports the result of the mutation analysis of MECP2 in 97 patients with classic or atypical RTT or RTT-like, conducted to obtain a genotypeic representation of the mutational spectrum in Taipei, Taiwan.atients and Methods: A total of 97 clinically suspicious RTT or RTT-like patients, referred to National Taiwan University Hospital for MECP2 gene mutation analysis, were involved in this study. Patients were grouping according to the clinical diagnostic criteria for the classic or variant Rett syndrome proposed by The Rett Syndrome Diagnostic Criteria Work Group (Hagberg et al. 2002), consisting of 23 classic, 37 atypical or RTT-like, and 37 grouped into idiopathic psychomotor retardation patients.The first group composed of RTT or RTT-like patients who were fulfilled the diagnostic criteria, and this group underwent DNA direct sequencing. In the mutation-negative patient, we used multiplex ligation-dependent probe amplification (MLPA) kit P015C to screen for large deletions. The other group who weren’t fulfill the classic or atypical RTT diagnostic criteria, were considered as idiopathic psychomotor retardation, but who may be related to the MECP2-related disorders were underwent MECP2-MLPA test directly to study the possible role of MECP2 duplication in this group.esults: Mutations in MECP2 were detected in 60.1% (14/23) of the patients presenting with classic RTT, and in 8.1% (3/37) of those with atypical RTT or RTT-like features. In total, 14 different MECP2 mutations, and 1 unclassified variant or mutation were identified in 17 of the 60 diagnosed as classical or atypical RTT or RTT-like patients. Most of the variants were missense mutations, accounting for 57.1% (8/14), followed by nonsense mutations 21.4% (3/14), and frame shift mutations 21.4% (3/14). We identified five novel mutations, four of which were point mutations, and one was deletion. The first, a nonsense mutation, C>T transition at the cDNA 844 (c.844C>T), lead to CGA change to TGA and became a stop codon (p.R282X). The other three were missense mutations (p.S149Y, p.V207M, p.Q437H), and one was a 83bp deletion (c.1117_1199del83) happened in exon 4 and lead to frameshift (p.S373fs). No mutations were found in exon 1 or 2 based on our study. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases. In the group of 37 patients with idiopathic psychomotor retardation, we identified one case with Xq28 duplication including MECP2 gene.onclusion: In Taiwan, most of the screenings are PCR-based and restricted to the coding part of the gene and therefore prone to miss gene dosage changes. To our knowledge, this is the first study in Taiwan to determine the role of large deletions of the MECP2 in RTT or RTT-like patients using MLPA method. Also, it is the first study in Taiwan to determine the possible role of duplications of the MECP2 region in children with psychomotor retardation using MLPA method. Although there was no large deletion of MECP2 found in our patients with Rett or Rett-like syndrome, it remains important to screen large deletions in these patients. Because duplication of MECP2 gene remains one of the possibilities in patients with psychomotor retardation of unknown etiology, we recommend screening MECP2 gene duplications in males with moderate to severe developmental delay, especially when a history of recurrent infections has been documented. We will continue our work to screen the large deletion of MECP2 gene in RTT or RTT-like patients, and the duplication of MECP2 gene in children with psychomotor retardation of unknown etiology to clarify the role of such changes in these patients.
Subjects
Rett syndrome
MECP2
Mutation analysis
SDGs
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