Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology
| Autor: | Julie Ruston, Jay Shendure, Christie M. Buchovecky, Elif Acar, Marijke Schrock, Adebola Enikanolaiye, Christine Taylor, Monica J. Justice, Rong Zeng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Candidate gene congenital hereditary and neonatal diseases and abnormalities Genotype DNA repair Methyl-CpG-Binding Protein 2 Mutagenesis (molecular biology technique) Biology medicine.disease_cause MECP2 03 medical and health sciences Mice 0302 clinical medicine Suppression Genetic Exome Sequencing Genetics medicine Rett Syndrome Animals Genetic Predisposition to Disease Gene Genetics (clinical) Alleles Genetic Association Studies 030304 developmental biology Suppressor mutation Mice Knockout 0303 health sciences Mutation Research Gene Expression Profiling Homozygote Lipid Metabolism Disease Models Animal Phenotype Female 030217 neurology & neurosurgery Genetic screen DNA Damage Signal Transduction |
| Zdroj: | Genome Res |
| Popis: | 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 categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT. |
| Databáze: | OpenAIRE |
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