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Research question:

Can therapeutic targets to ameliorate disease be identified through genetic modifier screens in mice? We chose as our model a mouse mutant that eliminates function of methyl CpG binding protein 2 (Mecp2), the gene mutated in most of the cases of Rett syndrome (RTT). RTT is a severe neurological disease with autistic features and developmental regression. In a forward genetic dominant screen, we randomly mutate a second genomic site in Mecp2-mutant mice to identify genes that suppress symptoms (two wrongs make a right). We have identified many lines carrying inherited suppressors that increase lifespan and decrease other RTT-related symptoms, and have identified important candidate genes. Massively parallel sequencing identifies mutations quickly and efficiently. One modifying mutation revealed that cholesterol synthesis was abnormal in Mecp2 mutants, and suggested that statin drug treatment would improve symptoms, leading to clinical trials. The ongoing screen discloses protein complexes significant for MECP2 function, but not identified in MECP2 DNA binding or protein interactions, and points to pathways for disease pathology. These studies open the field of Rett syndrome research, and broadly inform other neurological diseases. Our ultimate goal is to identify pharmacologically targetable alternatives that may ameliorate symptoms.

Project members:

Adebola Enikanolaiye – Research Fellow

Christine Taylor – Research Technologist

Julie Ruston – Project Manager

Laura Hergott – Graduate Student

Neeti Vashi – Graduate Student