Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology.

ABSTRACT: Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categorie

SUBMITTER: Enikanolaiye A 

PROVIDER: S-EPMC7197480 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature