TY - JOUR
T1 - Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders
AU - Mochel, Fanny
AU - Rastetter, Agnès
AU - Ceulemans, Berten
AU - Platzer, Konrad
AU - Yang, Sandra
AU - Shinde, Deepali N.
AU - Helbig, Katherine L.
AU - Lopergolo, Diego
AU - Mari, Francesca
AU - Renieri, Alessandra
AU - Benetti, Elisa
AU - Canitano, Roberto
AU - Waisfisz, Quinten
AU - Plomp, Astrid S.
AU - Huisman, Sylvia A.
AU - Wilson, Golder N.
AU - Cathey, Sara S.
AU - Louie, Raymond J.
AU - Del Gaudio, Daniela
AU - Waggoner, Darrel
AU - Kacker, Shawn
AU - Nugent, Kimberly M.
AU - Roeder, Elizabeth R.
AU - Bruel, Ange Line
AU - Thevenon, Julien
AU - Ehmke, Nadja
AU - Horn, Denise
AU - Holtgrewe, Manuel
AU - Kaiser, Frank J.
AU - Kamphausen, Susanne B.
AU - Abou Jamra, Rami
AU - Weckhuysen, Sarah
AU - Dalle, Carine
AU - Depienne, Christel
N1 - Publisher Copyright:
© 2020 The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100069408&partnerID=8YFLogxK
U2 - 10.1093/brain/awaa346
DO - 10.1093/brain/awaa346
M3 - Journal articles
C2 - 33242881
AN - SCOPUS:85100069408
SN - 0006-8950
VL - 143
SP - 3564
EP - 3573
JO - Brain
JF - Brain
IS - 12
ER -