P.134Physical and transcriptional characterization of human urinary stem cell populations

Abstract

S87 delay, intellectual disability, microcephaly, delayed brain myelination, and recurrent seizures, ultimately resulting in the death of most patients before the age of twenty. However, the function of UBA5 in the nervous system and how mutation of UBA5 results in disease was not known. To investigate the pathophysiology associated with UBA5 mutation and to identify pathways that could reduce disease progression we are using the zebrafish. We show that uba5 loss of function in zebrafish leads to significant decrease in locomotor activity, recapitulating the motor dysfunction observed in UBA5 patients. Notably, the motor impairment is not preceded by damage to the overall neuronal network and muscle morphology. However, electron microscopy reveals signs of degradation and aggregates in the nerves innervating the skeletal muscle of uba5 mutants. This finding suggests that there may be an early sub-clinical phenotype in the peripheral nervous system that could contribute to the pathology observed in UBA5 patients. We also identify a dramatic reduction in growth. We describe the identification of the pathways disrupted by the loss of Uba5 , explaining the epileptic symptoms, growth defects, and neurodegeneration observed in patients.