ArticleGenome medicine2022
Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.
Article in Genome medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 22 citations in OpenAlex.
- Expanding the Phenotypic and Functional Evidence for KCNK3 as a Neurodevelopmental Disorder Gene: A New Chinese Case and Drosophila Validation.Clinical genetics · 2026Article
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Equivalent gain-of-function variants in KCNK3 and KCNK9 and their contribution to distinct TASK K2P channelopathies.The Journal of general physiology · 2026Article
- Structural determinants for GPCR-mediated inhibition of TASK K2P channels by diacylglycerol and its dysfunction in disease.The EMBO journal · 2026Article
- Etiological Diagnosis and Disease Course of Birk-Barel Syndrome in an Adult Woman with aInternational medical case reports journal · 2026Article
- Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective.Brain sciences · 2025Review
- Genetic variants and phenotypic data curated for the CAGI6 intellectual disability panel challenge.Human genetics · 2025Article
- Structures of TASK-1 and TASK-3 K2P channels provide insight into their gating and dysfunction in disease.Structure (London, England : 1993) · 2025Article
- Assessing Protein Surface-Based Scoring for Interpreting Genomic Variants.International journal of molecular sciences · 2024Article
- Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort.International journal of molecular sciences · 2024Article
- Fine-tuning pH sensor H98 by remote essential residues in the hydrogen-bond network of mTASK-3.International journal of biological macromolecules · 2024Article
- C-type inactivation and proton modulation mechanisms of the TASK3 channel.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A rare early-onset neonatal case of Birk-Barel syndrome presenting severe obstructive sleep apnea: a case report.Frontiers in medicine · 2023Article
- AFrontiers in pharmacology · 2022Article
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Authors and funding
71 authors at 20 institutions in 9 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGenomics 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.
methodsThis 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.
resultsWe 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.
conclusionsThis 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.
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