Phil Jensik, PhD

Recent studies indicate that individuals with heritable and de novo mutations in the DEAF1 gene have intellectual disabilities, speech disorders and autism spectrum disorders.  We have collectively termed the intellectual disability and ASD-related neurodevelopmental anomalies observed in individuals with DEAF1 mutations as DEAF1-associated neurodevelopmental disorder (DAND).  The mechanisms by which de novo or heritable DEAF1 mutations alter neuronal development and cognitive function remain unclear.  Since DEAF1 is a transcription factor it is likely that changes in DEAF1-target gene expression cause the resultant cognitive function impairments.  

Our long-term research objective is to characterize the roles of DEAF1 in cognitive development, and the mechanisms by which DEAF1 mutations cause DAND.  In order to achieve this objective, we approach DEAF1/DAND research using 3 different model systems including I) genetic and clinical information from patients with DEAF1 mutations, II) Deaf1/DAND mouse models, and III) cellular and molecular model systems of DAND.  Through collaborations with clinicians, we have obtained genetic information from patients with mutations in the DEAF1 gene.  In total, we have functionally characterized ~60 DEAF1 variants.  

Not only does this data provide important structure-function information on the effects of specific DEAF1 amino acids, it also is used by the clinician to help diagnose the genetic cause of the disorder.  Deaf1 deficient mouse models have allowed us to study the effects of decreased DEAF1 protein expression on downstream gene expression and learning and memory.  

Currently, we have developed 2 new DAND knock-in mouse models that express different analogous mutations identified in individuals with DAND, and are assessing neurobehavioral and transcriptomic changes in these DAND models.  

In summary, the combination of identified DEAF1 mutation human data, Deaf1 mouse models, and in vitro approaches (cell and molecular) has begun to shed light on the importance of DEAF1 in cognitive function and development. This work is helping to address the question what is DAND as well as connecting DEAF1 to numerous other NDD and ASD causing genes.