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

Margot A. Cousin, Emma L. Veale, Nikita R. Dsouza, Swarnendu Tripathi, Robyn G. Holden, Maria Arelin, Geoffrey Beek, Mir Reza Bekheirnia, Jasmin Beygo, Vikas Bhambhani, Martin Bialer, Stefania Bigoni, Cyrus Boelman, Jenny Carmichael, Thomas Courtin, Benjamin Cogne, Ivana Dabaj, Diane Doummar, Laura Fazilleau, Alessandra FerliniRalitza H. Gavrilova, John M. Graham, Tobias B. Haack, Jane Juusola, Sarina G. Kant, Saima Kayani, Boris Keren, Petra Ketteler, Chiara Klöckner, Tamara T. Koopmann, Teresa M. Kruisselbrink, Alma Kuechler, Laëtitia Lambert, Xénia Latypova, Robert Roger Lebel, Magalie S. Leduc, Emanuela Leonardi, Andrea M. Lewis, Wendy Liew, Keren Machol, Samir Mardini, Kirsty McWalter, Cyril Mignot, Julie McLaughlin, Alessandra Murgia, Vinodh Narayanan, Caroline Nava, Sonja Neuser, Mathilde Nizon, Davide Ognibene, Joohyun Park, Konrad Platzer, Céline Poirsier, Maximilian Radtke, Keri Ramsey, Cassandra K. Runke, Maria J. Guillen Sacoto, Fernando Scaglia, Marwan Shinawi, Stephanie Spranger, Ee Shien Tan, John Taylor, Anne Sophie Trentesaux, Filippo Vairo, Rebecca Willaert, Neda Zadeh, Raul Urrutia, Dusica Babovic-Vuksanovic, Michael T. Zimmermann, Alistair Mathie, Eric W. Klee*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number62
JournalGenome Medicine
Issue number1
Publication statusPublished - 13 Jun 2022

Bibliographical note

Funding Information:
TBH was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—418081722, 433158657. MAC, TMK, FV, and EWK are supported by the Center for Individualized Medicine at Mayo Clinic. RU, NRD, ST, and MTZ were supported by The Linda T. and John A. Mellowes Endowed Innovation and Discovery Fund, the Genomic Sciences and Precision Medicine Center of Medical College of Wisconsin, and the Advancing a Healthier Wisconsin (AHW) Endowment.

Publisher Copyright: © 2022, The Author(s).


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