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

Fanny Mochel, Agnès Rastetter, Berten Ceulemans, Konrad Platzer, Sandra Yang, Deepali N. Shinde, Katherine L. Helbig, Diego Lopergolo, Francesca Mari, Alessandra Renieri, Elisa Benetti, Roberto Canitano, Quinten Waisfisz, Astrid S. Plomp, Sylvia A. Huisman, Golder N. Wilson, Sara S. Cathey, Raymond J. Louie, Daniela Del Gaudio, Darrel WaggonerShawn Kacker, Kimberly M. Nugent, Elizabeth R. Roeder, Ange Line Bruel, Julien Thevenon, Nadja Ehmke, Denise Horn, Manuel Holtgrewe, Frank J. Kaiser, Susanne B. Kamphausen, Rami Abou Jamra, Sarah Weckhuysen, Carine Dalle, Christel Depienne*

*Korrespondierende/r Autor/-in für diese Arbeit


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.

Seiten (von - bis)3564-3573
PublikationsstatusVeröffentlicht - 01.12.2020

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  • Querschnittsbereich: Medizinische Genetik


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