Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome
Abstract 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 des...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-06-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-022-01064-4 |
| _version_ | 1811343661871398912 |
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| author | 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 Ferlini Ralitza 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 |
| author_facet | 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 Ferlini Ralitza 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 |
| author_sort | Margot A. Cousin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T19:33:52Z |
| format | Article |
| id | doaj.art-e3306fa1990545148f66b913263d56ba |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-13T19:33:52Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-e3306fa1990545148f66b913263d56ba2022-12-22T02:33:07ZengBMCGenome Medicine1756-994X2022-06-0114111910.1186/s13073-022-01064-4Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndromeMargot A. Cousin0Emma L. Veale1Nikita R. Dsouza2Swarnendu Tripathi3Robyn G. Holden4Maria Arelin5Geoffrey Beek6Mir Reza Bekheirnia7Jasmin Beygo8Vikas Bhambhani9Martin Bialer10Stefania Bigoni11Cyrus Boelman12Jenny Carmichael13Thomas Courtin14Benjamin Cogne15Ivana Dabaj16Diane Doummar17Laura Fazilleau18Alessandra Ferlini19Ralitza H. Gavrilova20John M. Graham21Tobias B. Haack22Jane Juusola23Sarina G. Kant24Saima Kayani25Boris Keren26Petra Ketteler27Chiara Klöckner28Tamara T. Koopmann29Teresa M. Kruisselbrink30Alma Kuechler31Laëtitia Lambert32Xénia Latypova33Robert Roger Lebel34Magalie S. Leduc35Emanuela Leonardi36Andrea M. Lewis37Wendy Liew38Keren Machol39Samir Mardini40Kirsty McWalter41Cyril Mignot42Julie McLaughlin43Alessandra Murgia44Vinodh Narayanan45Caroline Nava46Sonja Neuser47Mathilde Nizon48Davide Ognibene49Joohyun Park50Konrad Platzer51Céline Poirsier52Maximilian Radtke53Keri Ramsey54Cassandra K. Runke55Maria J. Guillen Sacoto56Fernando Scaglia57Marwan Shinawi58Stephanie Spranger59Ee Shien Tan60John Taylor61Anne-Sophie Trentesaux62Filippo Vairo63Rebecca Willaert64Neda Zadeh65Raul Urrutia66Dusica Babovic-Vuksanovic67Michael T. Zimmermann68Alistair Mathie69Eric W. Klee70Department of Quantitative Health Sciences, Mayo ClinicMedway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham MaritimeBioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of WisconsinBioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of WisconsinMedway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham MaritimeDepartment for Women and Child Health, Hospital for Children and Adolescents, University Hospitals, University of LeipzigChildren’s Hospital of MinnesotaDepartment of Molecular and Human Genetics, Baylor College of MedicineInstitute of Human Genetics, University Hospital Essen, University of Duisburg-EssenChildren’s Hospital of MinnesotaDivision of Medical Genetics, Northwell HealthMedical Genetics Unit, Department of Medical Sciences, Ferrara UniversityDivision of Neurology, BC Children’s HospitalOxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic centre, Oxford University Hospitals NHS Foundation TrustDépartement of Genetics, APHP, Hôpital Pitié-Salpêtrière, Sorbonne UniversitéCHU Nantes, Service de génétique médicaleCHU de Rouen, Service de Néonatologie, Réanimation pédiatrique, Neuropédiatrie et éducation fonctionnelle de l’enfant, INSERM U 1245, ED497APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEPService de Néonatologie, CHU de CaenMedical Genetics Unit, Department of Medical Sciences, Ferrara UniversityCenter for Individualized Medicine, Mayo ClinicDepartment of Pediatrics, Harbor-UCLA Medical Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLACentre for Rare Diseases, University of TübingenGeneDxDepartment of Clinical Genetics, Leiden University Medical CenterDepartments of Pediatrics and Neurology, University of Texas Southwestern Medical Center and Children’s HealthAPHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de ParisInstitute of Human Genetics, University Hospital Essen, University of Duisburg-EssenInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Clinical Genetics, Leiden University Medical CenterCenter for Individualized Medicine, Mayo ClinicInstitute of Human Genetics, University Hospital Essen, University of Duisburg-EssenService de Genetique Clinique, CHRU de NancyCHU Nantes, Service de génétique médicaleSection of Medical Genetics, SUNY Upstate University HospitalDepartment of Molecular and Human Genetics, Baylor College of MedicineMolecular Genetics of Neurodevelopmental Disorders, Department of Woman and Child Health, University of PadovaDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Paediatric Medicine, KK Women’s and Children’s Hospital, Mount Elizabeth HospitalDepartment of Molecular and Human Genetics, Baylor College of MedicineDivision of Plastic and Reconstructive Surgery, Mayo ClinicGeneDxAPHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de ParisDivision of Medical Genetics, Northwell HealthMolecular Genetics of Neurodevelopmental Disorders, Department of Woman and Child Health, University of PadovaCenter for Rare Childhood Disorders, Translational Genomics Research InstituteAPHP, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de ParisInstitute of Human Genetics, University of Leipzig Medical CenterCHU Nantes, Service de génétique médicaleMedical Genetics Unit, Department of Medical Sciences, Ferrara UniversityInstitute of Medical Genetics and Applied Genomics, University of TübingenInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Genetics, Reims University HospitalInstitute of Human Genetics, University of Leipzig Medical CenterCenter for Rare Childhood Disorders, Translational Genomics Research InstituteDepartment of Clinical Genomics, Mayo ClinicGeneDxDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of MedicinePractice of Human GeneticsDepartment of Paediatric Medicine, KK Women’s and Children’s Hospital, Mount Elizabeth HospitalOxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic centre, Oxford University Hospitals NHS Foundation TrustService de Néonatologie, CHU de CaenCenter for Individualized Medicine, Mayo ClinicGeneDxGenetics CenterBioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of WisconsinCenter for Individualized Medicine, Mayo ClinicBioinformatics Research and Development Laboratory, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of WisconsinMedway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Anson Building, Central Avenue, Chatham MaritimeDepartment of Quantitative Health Sciences, Mayo ClinicAbstract 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.https://doi.org/10.1186/s13073-022-01064-4KCNK9 imprinting syndromeTASK3 channelNeurodevelopmental disorderElectrophysiologyComputational protein modeling |
| spellingShingle | 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 Ferlini Ralitza 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 Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome Genome Medicine KCNK9 imprinting syndrome TASK3 channel Neurodevelopmental disorder Electrophysiology Computational protein modeling |
| title | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
| title_full | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
| title_fullStr | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
| title_full_unstemmed | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
| title_short | Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
| title_sort | gain and loss of task3 channel function and its regulation by novel variation cause kcnk9 imprinting syndrome |
| topic | KCNK9 imprinting syndrome TASK3 channel Neurodevelopmental disorder Electrophysiology Computational protein modeling |
| url | https://doi.org/10.1186/s13073-022-01064-4 |
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