There is a fundamental gap in understanding how the underlying mutation leads to a recently identified disease called UBTF E210K Neuroregression Syndrome (UNS), a debilitating neurodevelopmental disorder. UNS is associated with a variant of UBTF, a transcriptional regulatory protein, in which glutamic acid at reside 210 is mutated to a lysine (E210K). The onset of UNS is about 2.5 to 3 years of age. In order to study UNS, we have generated a UBTF+/E210K mouse as a novel animal model of this disease. Increased comprehension of disease progression will identify the pathways and molecules that could serve the role of potential therapeutic targets. The long-term goal is to develop therapeutic intervention that decrease morbidity of this devastating illness. The objective in this application is to examine the histopathology of the brain in UBTF+/E210K and UBTFE210K/E210K mice at different ages, and the gene expression profiles in the cerebellum and cortex of WT and UBTF+/E210K mice. The central hypothesis is that increased levels of DNA damage and apoptosis will correlate with sensorimotor, behavioral and neurological phenotypes. The experiments in this proposal will be guided by two Specific Aims: 1) Examine and compare the histopathology and gene expression profile of brains from UBTF+/+ (wild-type), UBTF+/E210K, and UBTFE210K/E210K mice during disease progression. and 2) Identify the brain regions and cell populations implicated in sensorimotor and cognitive dysfunction. In the first aim, cellular characteristics such as DNA damage, apoptosis and gene expression profile will be monitored in brains from wild-type and mutant mice at different ages. In the second aim, we will identify the brain regions and vulnerable cell populations and corelate with behavioral abnormalities. The approach is innovative because disease progression of UNS is poorly understood and we take advantage of a novel mouse model to overcome the issues with performing these experiments in a human system. The proposed research is significant because it is expected to substantially advance our understanding of disease progression and identify potential pathways and molecules that are the most likely targets of disease modifying intervention for the debilitating UTBF E210K Neuroregression Syndrome.
The proposed research is relevant to public health because UBTF E210K Neuroregression Syndrome is a debilitating disease for which the genetic basis was recently identified but disease progression from the pathologic allele to the cellular abnormalities and intellectual and behavioral disabilities is poorly understood. Currently, there is no known disease--modifying therapeutics. Thus, the proposed research is relevant to the NIH?s mission because characterizing both the histopathology of brains and the gene expression profiles from mice carrying the UBTF E210K allele may lead to the identification of potential therapeutic targets and improvement in the quality of life for individuals affected with UBTF E210K Neuroregression Syndrome.