ICNC Abstracts, ICNC 2018

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Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport
heba youssef el khashab, Farrukh ABBAS Chaudhry

Last modified: 2018-09-09


Progressive myoclonus epilepsy is group of disorders characterized by myoclonic  tonic-clonic seizures, ataxia and cognitive decline. We  present two affected brothers. At 9 months of age  elder brother developed ataxia and myoclonic jerks. In second year he lost  ability to walk and talk, and  developed drug-resistant progressive myoclonus epilepsy. The cerebrospinal fluid level of glutamate was decreased while glutamine was increased. His younger brother manifested similar symptoms from 6 months of age. By exome sequencing of the proband we identified a novel homozygous frameshift variant in the potassium channel tetramerization domain 7 (KCTD7) gene (NM_153033.1:c.696delT: p.F232fs), which results in a truncated protein. The identified F232fs variant is inherited in autosomal recessive manner,  the healthy consanguineous parents carry the variant in  heterozygous state. Bioinformatic analyses  structure modelling showed that KCTD7 is  highly conserved protein, structurally similar to KCTD5 and several voltage-gated potassium channels, and that it may form homo- or heteromultimers. By heterologous expression in Xenopus laevis oocytes, we demonstrate that wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner and regulates activity of the neuronal glutamine transporter SAT2 (Slc38a2), while the F232fs variant impairs K+ fluxes and obliterates SAT2-dependent glutamine transport. Thus, our data demonstrate that KCTD7 has an impact on K+ fluxes, neurotransmitter synthesis and neuronal function, and that malfunction of the encoded protein may lead to progressive myoclonus epilepsy.


Kv channel; BTB/POZ domain; KCTD7; Slc38; PME

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