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, 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

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
JournalAmerican Journal of Human Genetics
DOIs
StateAccepted/In press - 2017

Fingerprint

Exome
Potassium Channels
Brain Diseases
Missense Mutation
Intellectual Disability
Anura
Oocytes
Epilepsy
Mutation
Brain
Genes

Keywords

  • Epilepsy
  • Epileptic encephalopathy
  • Intellectual disability
  • KCNQ5
  • Kv7.5
  • Potassium channels

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. / Lehman, Anna; Thouta, Samrat; Mancini, Grazia M.S.; Naidu, Sakkubai; van Slegtenhorst, Marjon; McWalter, Kirsty; Person, Richard; Mwenifumbo, Jill; Salvarinova, Ramona; Guella, Ilaria; McKenzie, Marna B.; Datta, Anita; Connolly, Mary B.; Kalkhoran, Somayeh Mojard; Poburko, Damon; Friedman, Jan M.; Farrer, Matthew J.; Demos, Michelle; Desai, Sonal; Claydon, Thomas.

In: American Journal of Human Genetics, 2017.

Research output: Research - peer-reviewArticle

Lehman, A, Thouta, S, Mancini, GMS, Naidu, S, van Slegtenhorst, M, McWalter, K, Person, R, Mwenifumbo, J, Salvarinova, R, Guella, I, McKenzie, MB, Datta, A, Connolly, MB, Kalkhoran, SM, Poburko, D, Friedman, JM, Farrer, MJ, Demos, M, Desai, S & Claydon, T 2017, 'Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy' American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2017.05.016
Lehman, Anna ; Thouta, Samrat ; Mancini, Grazia M.S. ; Naidu, Sakkubai ; van Slegtenhorst, Marjon ; McWalter, Kirsty ; Person, Richard ; Mwenifumbo, Jill ; Salvarinova, Ramona ; Guella, Ilaria ; McKenzie, Marna B. ; Datta, Anita ; Connolly, Mary B. ; Kalkhoran, Somayeh Mojard ; Poburko, Damon ; Friedman, Jan M. ; Farrer, Matthew J. ; Demos, Michelle ; Desai, Sonal ; Claydon, Thomas. / Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. In: American Journal of Human Genetics. 2017
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AU - Lehman,Anna

AU - Thouta,Samrat

AU - Mancini,Grazia M.S.

AU - Naidu,Sakkubai

AU - van Slegtenhorst,Marjon

AU - McWalter,Kirsty

AU - Person,Richard

AU - Mwenifumbo,Jill

AU - Salvarinova,Ramona

AU - Guella,Ilaria

AU - McKenzie,Marna B.

AU - Datta,Anita

AU - Connolly,Mary B.

AU - Kalkhoran,Somayeh Mojard

AU - Poburko,Damon

AU - Friedman,Jan M.

AU - Farrer,Matthew J.

AU - Demos,Michelle

AU - Desai,Sonal

AU - Claydon,Thomas

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AB - 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.

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KW - Epileptic encephalopathy

KW - Intellectual disability

KW - KCNQ5

KW - Kv7.5

KW - Potassium channels

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