2. Academic Validation
  3. Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

  • Am J Hum Genet. 2017 Jul 6;101(1):65-74. doi: 10.1016/j.ajhg.2017.05.016.
Anna Lehman 1,  Samrat Thouta 2,  Grazia M S Mancini 3,  Sakkubai Naidu 4,  Marjon van Slegtenhorst 3,  Kirsty McWalter 5,  Richard Person 5,  Jill Mwenifumbo 6,  Ramona Salvarinova 7,  CAUSES Study 8,  EPGEN Study 8,  Ilaria Guella 9,  Marna B McKenzie 9,  Anita Datta 10,  Mary B Connolly 10,  Somayeh Mojard Kalkhoran 2,  Damon Poburko 2,  Jan M Friedman 6,  Matthew J Farrer 11,  Michelle Demos 10,  Sonal Desai 4,  Thomas Claydon 12
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada. Electronic address: alehman@cw.bc.ca.
  • 2 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • 3 Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
  • 4 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21211, USA.
  • 5 GeneDx, Gaithersburg, MD 20877 USA.
  • 6 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 7 Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 8 University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 9 Centre for Applied Neurogenetics, University of British Columbia, Vancouver BC, V6T 1Z3, Canada.
  • 10 Division of Pediatric Neurology, Department of Pediatrics, University of British Columbia, Vancouver BC, V6H 3N1, Canada.
  • 11 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Centre for Applied Neurogenetics, University of British Columbia, Vancouver BC, V6T 1Z3, Canada.
  • 12 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada. Electronic address: thomas_claydon@sfu.ca.
PMID: 28669405 DOI: 10.1016/j.ajhg.2017.05.016
Abstract

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome Sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this Potassium Channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.

Keywords

KCNQ5; Kv7.5; epilepsy; epileptic encephalopathy; intellectual disability; potassium channels.

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