POSTER NO: 461

MECP2 gene mutation analysis of Rett syndrome in China

¹Yanping Wang, ²Hong Pan, ²Xinhua Bao, ²Hongdi Meng, ³Yan Zhang, ²Xiru Wu, ¹Yan Shen
¹Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), #5 Dong Dan San Tiao, Beijing, 100005, P.R. China, ²Department of Pediatrics, First Hospital of Peking University, #1 Xi An Men Street, Beijing, 100034, P.R. China, ³Chinese National Human Genome Center, Beijing, #3-707 North Yong Chang Road, Beijing, 100176, P.R. China

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder that almost exclusively affects girls with an estimated prevalence of approximately 1 in 10,000-15,000 females. Patients with classical RTT appear to develop normally until 6-18 months of life. They then lose acquired speech and purposeful hand use gradually, followed by decelerated head growth and development of seizures, autistic features, ataxia, gait apraxia and respiratory dysfunction. Repetitive, stereotyped hand movements appear during the neurological regression and are the hallmark of the disease. The X-linked methyl-CpG-binding protein 2 (MeCP2) gene has been identified responsible for this disorder. MeCP2 is a global transcriptional repressor and abundant in the brain. It includes 486 amino acids, encoded by three exons. MeCP2 specifically binds with its methyl-binding domain (MBD) to symmetrically positioned methylated CpG dinucleotides. Its transcriptional repression domain (TRD) recruits a co-repressor complex containing SIN3A and histone deacetylases and results in the repression of the target gene. Methylation of CpG in the mammalian genome is important for silencing transcription in processes such as X-inactivation, imprinting and the control of tissue specific gene expression. Decreased MeCP2 activity will lead to derepression of transcription at multiple CNS loci and overexpression of some genes that may be detrimental during brain development. A lot of mutations have been detected in different races recently. In this study, thirty-one sporadic Chinese cases of classical RTT have been followed up, and their MECP2 genes were analysed. The patients were diagnosed between the age of 1 year 6 months and 5 years. Presently, the patients were between 3 and 19 years old and their mean age was 10.6 years old. They were located in 9 provinces. Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes of patients. We employed PCR and direct sequencing to analyze the MECP2 gene coding region in sporadic RTT Chinese cases. Twelve different mutations were identified. The characterized mutations were all in the third exon and were heterozygous. There were four missense mutations, three nonsense mutations, five frameshift mutations (a single nucleotide deletion, a single nucleotide insertion, a double deletion and two large fragment deletions). Most missense mutations were located in highly conserved functional domains as revealed by comparing human, mouse, xenopus and chicken sequences. The large fragment deletion mutations were located in a hot spot for deletion that has been reported. Milder disease was observed in some cases carrying missense mutations as compared with those carrying truncating mutations. And truncating mutations within or downstream of TRD or deletions in the C-terminal region are consistent with reduced clinical severity when compared with truncating mutations N-terminal to this domain. Our results provide further evidence that mutations in MECP2 gene are considered to be a cause for Rett syndrome. Further studies should include the pathogenesis, more detailed correlation between genotype and phenotype, and the roles of MECP2 gene and MeCP2 protein in neurodevelopment. The further detection of noncoding regions, the promoter region and the 3UTR should be carried out, too.