CFIm Protein Complex in
As a postdoc I was interested in the regulation of MECP2, the gene that is mutated in Rett syndrome. MeCP2 is peculiar for having a very long (~8.5 kb) 3’UTR that contains two prominent poly-adenylation (p(A)) sites: a proximal p(A) and a distal p(A), resulting, respectively, in short and long messenger mRNA isoforms. Alternative polyadenylation (APA) gives rise to multiple mRNA isoforms of a gene's 3’UTRs, which are then acted upon by different post-transcriptional regulatory factors such as microRNAs (miRNAs) and RNA-binding proteins (RBPs).
We found that MeCP2 protein levels are regulated by the CFIm protein complex through these APA sites. We then identified eleven individuals with neuropsychiatric disease who have copy number variations (CNVs) spanning NUDT21, which encodes CFIm25. These individuals suffer from autism spectrum disorder and notable developmental regression, very similar to Rett syndrome. We thus discovered that NUDT21 duplication causes a new autism spectrum disorder (eLife, 2015). We are now seeking to understand the roles of the CFIm complex in other human neurological diseases.