ZGRF1 variants implicated in a sensory reflex epilepsy

Abstract

Hot water epilepsy (HWE) is a sensory reflex epilepsy in which seizures are precipitated by a stimulus such as contact with hot water. While there is a genetic basis to its etiology, identity of the genes underlying this relatively uncommon disorder has remained unknown. Here, we present the results of our studies aimed at identifying a causative gene in a south Indian four-generation family with several affected members. We conducted whole-exome sequencing and examined a known locus that maps to 4q24-q28 (HWE2, MIM: 613340) that we had previously identified. We identified a sequence variant, c.1805C>T (p.Thr602Ile) in ZGRF1, located within the HWE2 locus, co-segregating with the disorder. The transcript structure of ZGRF1 was examined in 288 HWE patients, and five additional missense variants, Arg326Gln, Glu660Gly, Arg1862*, Phe1940Leu and Asp1984Gly, present exclusively or almost exclusively in the patients were found. Functional correlates of the six variants identified were examined in cultured mammalian cells. We observed spindle pole defects during cell division and partially disrupted localization of UPF1, a protein involved in cell cycle regulation, at the spindles. Our observations provide insights into the genetic basis of HWE and suggest the involvement of hitherto unanticipated molecular process in this disorder.