Intellectual disability is characterized by below-average cognitive ability leading to significant deficits in functioning and adaptive behaviors. Th majority of the unexplained intellectual disability cases are caused by de novo gene mutations. Four individuals with intellectual disabilities were found to have heterozygous de novo point mutations within the DNA binding domain of the transcription factor Deformed Epidermal Autoregulatory Factor-1 (DEAF1), and the resultant amino acid substitutions were shown to negatively affect DEAF1 protein function. Four additional DEAF1 variants have recently been identified from a de-identified group of samples from individuals with intellectual disabilities an autism spectrum disorders. These mutations also occur within the DNA binding domain, but the effects of these mutations on DEAF1 function are currently uncharacterized. Since DEAF1 haploin sufficiency has not been reported to result in intellectual disabilities, this suggests tha the mutant DEAF1 proteins likely exert dominant negative influences on wildtype DEAF1 function. The underlying mechanisms by which mutant DEAF1 proteins contribute to the pathogenesis producing the intellectual disabilities remain unclear. The hypothesis for this proposal is that mutations in the DEAF1 gene that diminish DEAF1 protein function cause altered neuronal activity and measurable changes in target gene expression.
Specific Aim 1 will determine the effects of newly identified DEAF1 mutations on DEAF1 protein function and also assess dominant negative activity of the DEAF1 mutant proteins using both in vitro and ex vivo approaches.
Specific Aim 2 will evaluate the effects of diminished DEAF1 function on neuronal activity/plasticity and target gene expression. Mice with conditional knockout of Deaf1 in the brain show anxiety-like behavior and impaired contextual memory in fear-conditioning tests and will be used to establish a role of DEAF1 in regulating neuronal activity. DEAF1 gene targets related to neuronal and cognitive function that are differentially expressed in the hippocampus of these mice will be assessed. The proposed studies will describe the functional effects of identified human de novo DEAF1 mutations and the consequences of reduced DEAF1 activity in the central nervous system. We expect that the results of these studies will also provide evidence into the causal relationship between dysregulated DEAF1 function and intellectual disability.
The underlying causes for the majority of non-syndromic intellectual disabilities are currently unknown but are thought to occur because of new mutations in genes that regulate neuronal development and function. Newly identified mutations in the DEAF1 gene have been identified in individuals with moderate to severe intellectual disabilities. The proposed studies will determine the effects these mutations have on DEAF1 protein function, and how loss of DEAF1 gene expression produces defects in the area of the brain responsible for learning and memory.
|Chen, Li; Jensik, Philip J; Alaimo, Joseph T et al. (2017) Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype. Hum Mutat 38:1774-1785|
|Mullegama, Sureni V; Jensik, Phillip; Li, Chen et al. (2017) Coupling clinical exome sequencing with functional characterization studies to diagnose a patient with familial Mediterranean fever and MED13L haploinsufficiency syndromes. Clin Case Rep 5:833-840|