MeCP2_e2 does not contribute Rett syndrome phenotypes but essential for placenta

Abstract

Methyl CpG‐binding protein 2 (MeCP2) mutations are implicated in Rett syndrome (RTT). Two MeCP2 isoforms have been reported as MeCP2_e2 and MeCP2_e1. Their expression levels vary among tissues, with MeCP2_e1 in adult brain and with MeCP2_e2 in placenta, liver, and skeletal muscle.We performed specific disruption of the MeCP2_e2 and examined the consequences of selective loss of MeCP2_e2 function in vivo. MeCP2_e2 null mice showed no RTT‐associated neurological phenotypes but confers a survival disadvantage. In addition, selective loss of MeCP2_e2 resulted in placenta defects and upregulation of peg‐1 as determined by the parental origin of the mutant allele. It is indicated a novel role for MeCP2 in normal placenta development and illustrate how X chromosome inactivation in extraembryonic tissues confers a survival disadvantage for carriers of a mutant MeCP2_e2 allele. Moreover, our findings provide an explanation for the absence of reports on MeCP2_e2‐specific exon 2 mutations in RTT. MeCP2_e2 mutations in humans may result in a phenotype that evades a diagnosis of RTT.