DESCRIPTION (provided by applicant): The Undiagnosed Disease Network (UDN) of the NIH has identified an individual presenting with severe neurological symptoms including microcephaly, progressive brain atrophy on MRI and global developmental delay. The UDN identified a specific mutation in the FOXR1 (forehead [FH] box protein R1) gene in this individual resulting in a non-synonymous protein alteration. FOXR1 is a member of the FH transcription factor family that in humans comprises at least 50 distinct human genes. The function of FOXR1 is currently unknown; however, several genes within the FOX family including FOXG1 and FOXP2 are critical for proper neuronal and brain development and mutations in FOXG1, FOXC2 and FOXL2 can also lead to microcephaly. Based on these observations, the central hypothesis of this application is that FOXR1 is a nuclear transcription factor that plays a central role in neuronal proliferation, differentiation and migration in the developing cortex. Therefore, our aims are to determine the role of FOXR1 in brain development and determine the molecular mechanism underlying FOXR1 function and how the FOXR1 mutation leads to disease pathogenesis. With innovative approaches such as molecular genetics including ChIP to identify transcriptional targets and in utero electroporation to obtain n vivo data, the proposed research will provide new insights into FOXR1 in brain development and disease pathogenesis. In addition, the results of this study may shed light on mechanisms relevant to the etiology of many neurological and psychiatric disorders related to cortical function.

PUBLIC HEALTH RELEVANCE: This study investigates the molecular and cellular mechanisms of human microcephaly, an important and under-investigated neurodevelopmental disorder. Understanding how microcephaly develops is important not only for a deeper understanding brain development, but also to advance our understanding and potential treatment of a variety of other neurodevelopmental disorders caused through defects in cerebral cortex development including mental retardation, epilepsy, autism, and schizophrenia.