title: Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport.
abstract: Progressive myoclonus epilepsy is a heterogeneous group of disorders characterized by myoclonic and tonic-clonic seizures, ataxia and cognitive decline. We here present two affected brothers. At 9 months of age the elder brother developed ataxia and myoclonic jerks. In his second year he lost the ability to walk and talk, and he 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 an autosomal recessive manner, and the healthy consanguineous parents carry the variant in a heterozygous state. Bioinformatic analyses and structure modelling showed that KCTD7 is a 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. Characterization of four additional disease-causing variants (R94W, R184C, N273I, Y276C) bolster these results and reveal the molecular mechanisms involved in the pathophysiology of KCTD7-related progressive myoclonus epilepsy. 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.
authors.affiliation: 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway.
authors.forename: Marivi Nabong
authors.initials: MN
authors.lastname: Moen
authors.affiliation: 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Roar
authors.initials: R
authors.lastname: Fjær
authors.affiliation: 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway.|3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
authors.forename: El Hassan
authors.initials: EH
authors.lastname: Hamdani
authors.affiliation: 4 Department of Microbiology, Oslo University Hospital, Oslo, Norway.|5 Bioinformatics Core Facility, Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Jon K
authors.initials: JK
authors.lastname: Laerdahl
authors.affiliation: 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway.
authors.forename: Robin Johansen
authors.initials: RJ
authors.lastname: Menchini
authors.affiliation: 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Magnus Dehli
authors.initials: MD
authors.lastname: Vigeland
authors.affiliation: 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Dag Erik
authors.initials: DE
authors.lastname: Undlien
authors.affiliation: 6 Department of Complex Neurology and Neurohabilitation, Oslo University Hospital, Oslo, Norway.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Hassel
authors.affiliation: 7 Division of Paediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: 7 Division of Paediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.|8 Department of Paediatrics, Ain Shams University, Cairo, Egypt.
authors.forename: Heba Y
authors.initials: HY
authors.lastname: El Khashab
authors.affiliation: 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.|9 National Centre for Rare Epilepsy-related Disorders, Oslo University Hospital, Oslo, Norway.
authors.forename: Kaja Kristine
authors.initials: KK
authors.lastname: Selmer
authors.affiliation: 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway f.a.chaudhry@medisin.uio.no.|3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
authors.forename: Farrukh Abbas
authors.initials: FA
authors.lastname: Chaudhry
mesh_terms: D026924:Amino Acid Transport System A / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002675:Child, Preschool; D003241:Consanguinity; D017809:Fatal Outcome; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes; D010375:Pedigree; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics*; D012529:Saudi Arabia; D035781:Siblings; D014982:Xenopus laevis
chemical_list: D026924:Amino Acid Transport System A; C522280:KCTD7 protein, human; D015221:Potassium Channels; C498798:Slc38a2 protein, mouse; D005973:Glutamine; D011188:Potassium
keywords: BTB/POZ domain; KCTD7; Kv channel; PME; Slc38