2. Academic Validation
  3. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

  • Brain. 2020 Dec 1;143(12):3564-3573. doi: 10.1093/brain/awaa346.
Fanny Mochel 1 2,  Agnès Rastetter 1,  Berten Ceulemans 3,  Konrad Platzer 4,  Sandra Yang 5,  Deepali N Shinde 6,  Katherine L Helbig 7 8,  Diego Lopergolo 9 10,  Francesca Mari 9 10,  Alessandra Renieri 9 10,  Elisa Benetti 11,  Roberto Canitano 12,  Quinten Waisfisz 13,  Astrid S Plomp 13,  Sylvia A Huisman 14 15,  Golder N Wilson 16,  Sara S Cathey 17,  Raymond J Louie 18,  Daniela Del Gaudio 18,  Darrel Waggoner 18,  Shawn Kacker 19,  Kimberly M Nugent 20 21,  Elizabeth R Roeder 20 21,  Ange-Line Bruel 22 23,  Julien Thevenon 24 25,  Nadja Ehmke 26,  Denise Horn 26,  Manuel Holtgrewe 27,  Frank J Kaiser 28,  Susanne B Kamphausen 29,  Rami Abou Jamra 4,  Sarah Weckhuysen 30 31 32,  Carine Dalle 1,  Christel Depienne 1 28
Affiliations

Affiliations

  • 1 Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013 Paris, France.
  • 2 AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique and Centre de Référence Neurométabolique Adulte, F-75013, Paris, France.
  • 3 Division of Paediatric Neurology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
  • 4 Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
  • 5 GeneDx, Gaithersburg, MD 20877, USA.
  • 6 Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 7 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8 The Epilepsy Neurogenetics Initiative, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 9 Medical Genetics, University of Siena, Siena, Italy.
  • 10 Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
  • 11 Department of Medical Biotechnologies, University of Siena, Siena, Italy.
  • 12 Division of Child and Adolescent Neuropsychiatry, University Hospital of Siena, Siena, Italy.
  • 13 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 14 Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.
  • 15 Prinsenstichting, Purmerend, The Netherlands.
  • 16 Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, Texas, USA.
  • 17 Greenwood Genetic Center, Greenwood, South Carolina, 29646, USA.
  • 18 Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.
  • 19 Department of Pediatrics, Section of Child Neurology, University of Chicago, Chicago, IL, 60637, USA.
  • 20 Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, 78207, USA.
  • 21 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 22 UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
  • 23 Centre de référence maladies rares 'déficiences intellectuelles de causes rares', Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • 24 Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, 38700 La Tronche, France.
  • 25 INSERM 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38706 Grenoble, France.
  • 26 Institute for Human Genetics and Medical Genetics, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
  • 27 Core Unit Bioinformatics - CUBI, Berlin Institute of Health (BIH), Berlin, Germany.
  • 28 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
  • 29 Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
  • 30 Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • 31 Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
  • 32 Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
PMID: 33242881 DOI: 10.1093/brain/awaa346
Abstract

KCNN2 encodes the small conductance calcium-activated Potassium Channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Keywords

KCNN2; SK2 channel; ataxia; developmental delay; tremor.

Figures