Frameshift mutations of alter the sensory circuit function in .

A frameshift mutation in () was recently found from a rare human disorder with peripheral neurological conditions including hypotonia and areflexia. The YPEL gene family is highly conserved from yeast to human, but its members' functions are poorly defined. Moreover, the pathogenicity of the human variant is completely unknown. We generated a model of human variant and a genetic null allele of homolog of (referred to as ). Gene-trap analysis suggests that is predominantly expressed in subsets of neurons, including larval nociceptors. Analysis of chemical nociception induced by allyl-isothiocyanate (AITC), a natural chemical stimulant, revealed reduced nociceptive responses in both frameshift and null mutants. Subsequent circuit analysis showed reduced activation of second-order neurons (SONs) in the pathway without affecting nociceptor activation upon AITC treatment. Although the gross axonal and dendritic development of nociceptors was unaffected, the synaptic contact between nociceptors and SONs was decreased by the mutations. Furthermore, expressing dYPEL3 in larval nociceptors rescued the behavioral deficit in frameshift mutants, suggesting a presynaptic origin of the deficit. Together, these findings suggest that the frameshift mutation results in loss of function and may cause neurological conditions by weakening synaptic connections through presynaptic mechanisms.