Role of a BHLHB9 polymorphism in the etiology of a developmental disorder

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 DESCRIPTION (provided by applicant): High-throughput genome screening of patients provides hope for identifying biological mechanisms in rare, undiagnosed disorders, and may provide broader insight into more common disease categories. However, variant identification is only a first step; a cause-effect relationship between variant and phenotype must be established, and therapeutic strategy formulation requires a thorough understanding of cellular and protein pathologies. The NIH Undiagnosed Disease Program recently characterized a male patient, UDP1757 with neonatal onset of motor dysfunction, cognitive deficiencies, low brain volume, and peripheral neuropathy, worsening at 15 months, and who died at 10 years of age. Genetic screening showed a hemizygous single point mutation in the BHLHB9 locus (C318R) located on the X chromosome. BHLHB9 has been shown to prevent apoptosis and to promote neuronal differentiation and axonogenesis. We hypothesize that C318R results in a loss- or reduction-of-function mutation that results in increased neuronal cell death and reduced axon outgrowth, hence leading to cortical atrophy and broad-spectrum neural dysfunction. The objective of this proposal is to establish a role of the C318R mutation in abnormal neuronal death and reduced neuronal differentiation and axonogenesis. To do so, we propose in vitro assays involving modifications of the BHLHB9 gene in mouse neural stem cells and patient-derived, neutrally differentiated iPS cells in order to define cellular pathologies. We will additionally use mouse models in which Bhlhb9 mutations are introduced, behavioral phenotype determined, and CNS impact defined anatomically. We anticipate that the mouse will recapitulate the clinical phenotype of UDP1757, and that both cell assays and anatomical imaging will yield data consistent with our hypothesis that BHLHB9 C318R is a loss- or reduction-of-function mutation. A strength is a team of experts with complementary skills in pediatric genetics and rare diseases, genetic engineering, transgenic mouse and iPS cell technologies, rodent behavioral assessment, and neuronal culture and quantitation. Additionally, the proposal draws on the rich core resources of the Kansas Intellectual and Developmental Disabilities Research Center. This Exploratory/Developmental Research Grant Award will make significant contributions by establishing cellular processes responsible for an uncharacterized clinical phenotype, and will provide a basis for subsequent studies using the in vitro and in vivo tools developed in this study to formulate, screen and test therapeutic strategies to ameliorate this and related devastating developmental disorders.