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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, and others. (2022) Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. Genome Medicine, 14 (1). Article Number 62. E-ISSN 1756-994X. (doi:10.1186/s13073-022-01064-4) (KAR id:95466)


Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood.

Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies.

Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation.

Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

Item Type: Article
DOI/Identification number: 10.1186/s13073-022-01064-4
Uncontrolled keywords: KCNK9 imprinting syndrome; TASK3 channel; Neurodevelopmental disorders; Electrophysiology; Computational protein modeling
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Funders: Deutsche Forschungsgemeinschaft (
Depositing User: Alistair Mathie
Date Deposited: 16 Jun 2022 08:56 UTC
Last Modified: 04 Mar 2024 18:30 UTC
Resource URI: (The current URI for this page, for reference purposes)

University of Kent Author Information

Veale, Emma L..

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Holden, Robyn G..

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Mathie, Alistair.

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