Consistent with reduced neuronal growth and complexity in Rett syndrome (RTT) brains, overexpression of human MECP2 carrying missense mutations common in RTT individuals (R106W or T158M) reduced dendritic and axonal length.
Although more than 200 different MECP2 mutations have been identified throughout the gene, 7 of those (p.R133C, p.T158M, p.R168X, p.R255X, p.R270X, p.R294X, and p.R306C) account for up to two-thirds of pathogenic mutations in RTT patients.
The spectrum of MECP2 mutations within the mainland Chinese RTT patients is similar to that of those patients reported in the world. p.T158M, p.R168X, c.806delG, p.R255X, p.R270X, p.R133C, p.R306C, and p.R106W are the hotspot mutations of MECP2 and c.806delG is a specific hotspot mutation in Chinese patients with RTT.
There are relationships between MECP2 genotype and phenotype:the RTT patients with nonsense mutations located in MBD tend to develop more severe phenotype;there are significant differences in language skill and language impairment rate in the groups with p.T158M, p.R168X, c.806del and p.R255X, which had higher frequency in children below five-years of age and the p.R168X present with most severe impairment.
RTT females with the T158M missense mutation are often atypical with mainly behavioral characteristics in infancy and childhood but become classic RTT in adolescence after a slower, protracted course.
Here, we have shown that frequent RTT-causing missense mutations (R106W, R133C, F155S, T158M) located in the methylated DNA-binding domain (MBD) of MeCP2 have profound and diverse effects on its structure, stability, and DNA-binding properties.