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

Autor:	Enikanolaiye A; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada., Ruston J; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada., Zeng R; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada., Taylor C; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada., Schrock M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Buchovecky CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Shendure J; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.; Brotman Baty Institute for Precision Medicine, Seattle, Washington 98195, USA.; Allen Discovery Center for Cell Lineage Tracing, Seattle, Washington 98195, USA.; Howard Hughes Medical Institute, Seattle, Washington 98195, USA., Acar E; The Centre for Phenogenomics, Toronto, Ontario, M5T 3H7, Canada.; Department of Statistics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada., Justice MJ; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.; The Centre for Phenogenomics, Toronto, Ontario, M5T 3H7, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2020 Apr; Vol. 30 (4), pp. 540-552. Date of Electronic Publication: 2020 Apr 21.
DOI:	10.1101/gr.258400.119
Abstrakt:	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. (© 2020 Enikanolaiye et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu