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

Anna Lehman; Samrat Thouta; Grazia M S Mancini; Sakkubai Naidu; Marjon van Slegtenhorst; Kirsty McWalter; Richard Person; Jill Mwenifumbo; Ramona Salvarinova; CAUSES Study; EPGEN Study; Ilaria Guella; Marna B McKenzie; Anita Datta; Mary B Connolly; Somayeh Mojard Kalkhoran; Damon Poburko; Jan M Friedman; Matthew J Farrer; Michelle Demos; Sonal Desai; Thomas Claydon

doi:10.1016/j.ajhg.2017.05.016

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. Epub 2017 Jun 29.

Authors

Anna Lehman¹, Samrat Thouta², Grazia M S Mancini³, Sakkubai Naidu⁴, Marjon van Slegtenhorst³, Kirsty McWalter⁵, Richard Person⁵, Jill Mwenifumbo⁶, Ramona Salvarinova⁷; CAUSES Study⁸; EPGEN Study⁸; Ilaria Guella⁹, Marna B McKenzie⁹, Anita Datta¹⁰, Mary B Connolly¹⁰, Somayeh Mojard Kalkhoran², Damon Poburko², Jan M Friedman⁶, Matthew J Farrer¹¹, Michelle Demos¹⁰, Sonal Desai⁴, Thomas Claydon¹²

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.

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.

MeSH terms

Electroencephalography
Epilepsy / genetics*
Genetic Predisposition to Disease*
Humans
Intellectual Disability / genetics*
Ion Channel Gating
KCNQ Potassium Channels / chemistry
KCNQ Potassium Channels / genetics*
Mutant Proteins / chemistry
Mutant Proteins / genetics
Mutation / genetics*
Phenotype
Sequence Alignment

Substances

KCNQ Potassium Channels
KCNQ5 protein, human
Mutant Proteins