Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome
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 an...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Cousin, Margot A. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2022 |
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| Übergeordnetes Werk: |
Enthalten in: Genome medicine - London : BioMed Central, 2009, 14(2022), 1 vom: 13. Juni |
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| Übergeordnetes Werk: |
volume:14 ; year:2022 ; number:1 ; day:13 ; month:06 |
| Links: |
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| DOI / URN: |
10.1186/s13073-022-01064-4 |
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| Katalog-ID: |
SPR050781634 |
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| 100 | 1 | |a Cousin, Margot A. |e verfasserin |0 (orcid)0000-0002-6119-9346 |4 aut | |
| 245 | 1 | 0 | |a Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
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| 520 | |a 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. | ||
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10.1186/s13073-022-01064-4 doi (DE-627)SPR050781634 (SPR)s13073-022-01064-4-e DE-627 ger DE-627 rakwb eng Cousin, Margot A. verfasserin (orcid)0000-0002-6119-9346 aut Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 Veale, Emma L. (orcid)0000-0002-6778-9929 aut Dsouza, Nikita R. aut Tripathi, Swarnendu aut Holden, Robyn G. aut Arelin, Maria aut Beek, Geoffrey aut Bekheirnia, Mir Reza aut Beygo, Jasmin aut Bhambhani, Vikas aut Bialer, Martin aut Bigoni, Stefania aut Boelman, Cyrus aut Carmichael, Jenny aut Courtin, Thomas aut Cogne, Benjamin aut Dabaj, Ivana aut Doummar, Diane aut Fazilleau, Laura aut Ferlini, Alessandra (orcid)0000-0001-8385-9870 aut Gavrilova, Ralitza H. aut Graham, John M. aut Haack, Tobias B. aut Juusola, Jane aut Kant, Sarina G. aut Kayani, Saima aut Keren, Boris aut Ketteler, Petra aut Klöckner, Chiara aut Koopmann, Tamara T. aut Kruisselbrink, Teresa M. aut Kuechler, Alma aut Lambert, Laëtitia aut Latypova, Xénia aut Lebel, Robert Roger aut Leduc, Magalie S. aut Leonardi, Emanuela aut Lewis, Andrea M. aut Liew, Wendy aut Machol, Keren aut Mardini, Samir aut McWalter, Kirsty aut Mignot, Cyril aut McLaughlin, Julie aut Murgia, Alessandra aut Narayanan, Vinodh aut Nava, Caroline aut Neuser, Sonja aut Nizon, Mathilde aut Ognibene, Davide aut Park, Joohyun aut Platzer, Konrad (orcid)0000-0001-6127-6308 aut Poirsier, Céline aut Radtke, Maximilian aut Ramsey, Keri aut Runke, Cassandra K. aut Guillen Sacoto, Maria J. aut Scaglia, Fernando aut Shinawi, Marwan aut Spranger, Stephanie aut Tan, Ee Shien aut Taylor, John aut Trentesaux, Anne-Sophie aut Vairo, Filippo aut Willaert, Rebecca aut Zadeh, Neda aut Urrutia, Raul aut Babovic-Vuksanovic, Dusica aut Zimmermann, Michael T. (orcid)0000-0001-7073-0525 aut Mathie, Alistair (orcid)0000-0001-6094-2890 aut Klee, Eric W. (orcid)0000-0003-2946-5795 aut Enthalten in Genome medicine London : BioMed Central, 2009 14(2022), 1 vom: 13. 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10.1186/s13073-022-01064-4 doi (DE-627)SPR050781634 (SPR)s13073-022-01064-4-e DE-627 ger DE-627 rakwb eng Cousin, Margot A. verfasserin (orcid)0000-0002-6119-9346 aut Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 Veale, Emma L. (orcid)0000-0002-6778-9929 aut Dsouza, Nikita R. aut Tripathi, Swarnendu aut Holden, Robyn G. aut Arelin, Maria aut Beek, Geoffrey aut Bekheirnia, Mir Reza aut Beygo, Jasmin aut Bhambhani, Vikas aut Bialer, Martin aut Bigoni, Stefania aut Boelman, Cyrus aut Carmichael, Jenny aut Courtin, Thomas aut Cogne, Benjamin aut Dabaj, Ivana aut Doummar, Diane aut Fazilleau, Laura aut Ferlini, Alessandra (orcid)0000-0001-8385-9870 aut Gavrilova, Ralitza H. aut Graham, John M. aut Haack, Tobias B. aut Juusola, Jane aut Kant, Sarina G. aut Kayani, Saima aut Keren, Boris aut Ketteler, Petra aut Klöckner, Chiara aut Koopmann, Tamara T. aut Kruisselbrink, Teresa M. aut Kuechler, Alma aut Lambert, Laëtitia aut Latypova, Xénia aut Lebel, Robert Roger aut Leduc, Magalie S. aut Leonardi, Emanuela aut Lewis, Andrea M. aut Liew, Wendy aut Machol, Keren aut Mardini, Samir aut McWalter, Kirsty aut Mignot, Cyril aut McLaughlin, Julie aut Murgia, Alessandra aut Narayanan, Vinodh aut Nava, Caroline aut Neuser, Sonja aut Nizon, Mathilde aut Ognibene, Davide aut Park, Joohyun aut Platzer, Konrad (orcid)0000-0001-6127-6308 aut Poirsier, Céline aut Radtke, Maximilian aut Ramsey, Keri aut Runke, Cassandra K. aut Guillen Sacoto, Maria J. aut Scaglia, Fernando aut Shinawi, Marwan aut Spranger, Stephanie aut Tan, Ee Shien aut Taylor, John aut Trentesaux, Anne-Sophie aut Vairo, Filippo aut Willaert, Rebecca aut Zadeh, Neda aut Urrutia, Raul aut Babovic-Vuksanovic, Dusica aut Zimmermann, Michael T. (orcid)0000-0001-7073-0525 aut Mathie, Alistair (orcid)0000-0001-6094-2890 aut Klee, Eric W. (orcid)0000-0003-2946-5795 aut Enthalten in Genome medicine London : BioMed Central, 2009 14(2022), 1 vom: 13. 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10.1186/s13073-022-01064-4 doi (DE-627)SPR050781634 (SPR)s13073-022-01064-4-e DE-627 ger DE-627 rakwb eng Cousin, Margot A. verfasserin (orcid)0000-0002-6119-9346 aut Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 Veale, Emma L. (orcid)0000-0002-6778-9929 aut Dsouza, Nikita R. aut Tripathi, Swarnendu aut Holden, Robyn G. aut Arelin, Maria aut Beek, Geoffrey aut Bekheirnia, Mir Reza aut Beygo, Jasmin aut Bhambhani, Vikas aut Bialer, Martin aut Bigoni, Stefania aut Boelman, Cyrus aut Carmichael, Jenny aut Courtin, Thomas aut Cogne, Benjamin aut Dabaj, Ivana aut Doummar, Diane aut Fazilleau, Laura aut Ferlini, Alessandra (orcid)0000-0001-8385-9870 aut Gavrilova, Ralitza H. aut Graham, John M. aut Haack, Tobias B. aut Juusola, Jane aut Kant, Sarina G. aut Kayani, Saima aut Keren, Boris aut Ketteler, Petra aut Klöckner, Chiara aut Koopmann, Tamara T. aut Kruisselbrink, Teresa M. aut Kuechler, Alma aut Lambert, Laëtitia aut Latypova, Xénia aut Lebel, Robert Roger aut Leduc, Magalie S. aut Leonardi, Emanuela aut Lewis, Andrea M. aut Liew, Wendy aut Machol, Keren aut Mardini, Samir aut McWalter, Kirsty aut Mignot, Cyril aut McLaughlin, Julie aut Murgia, Alessandra aut Narayanan, Vinodh aut Nava, Caroline aut Neuser, Sonja aut Nizon, Mathilde aut Ognibene, Davide aut Park, Joohyun aut Platzer, Konrad (orcid)0000-0001-6127-6308 aut Poirsier, Céline aut Radtke, Maximilian aut Ramsey, Keri aut Runke, Cassandra K. aut Guillen Sacoto, Maria J. aut Scaglia, Fernando aut Shinawi, Marwan aut Spranger, Stephanie aut Tan, Ee Shien aut Taylor, John aut Trentesaux, Anne-Sophie aut Vairo, Filippo aut Willaert, Rebecca aut Zadeh, Neda aut Urrutia, Raul aut Babovic-Vuksanovic, Dusica aut Zimmermann, Michael T. 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Juni (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:14 year:2022 number:1 day:13 month:06 https://dx.doi.org/10.1186/s13073-022-01064-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 13 06 |
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10.1186/s13073-022-01064-4 doi (DE-627)SPR050781634 (SPR)s13073-022-01064-4-e DE-627 ger DE-627 rakwb eng Cousin, Margot A. verfasserin (orcid)0000-0002-6119-9346 aut Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 Veale, Emma L. (orcid)0000-0002-6778-9929 aut Dsouza, Nikita R. aut Tripathi, Swarnendu aut Holden, Robyn G. aut Arelin, Maria aut Beek, Geoffrey aut Bekheirnia, Mir Reza aut Beygo, Jasmin aut Bhambhani, Vikas aut Bialer, Martin aut Bigoni, Stefania aut Boelman, Cyrus aut Carmichael, Jenny aut Courtin, Thomas aut Cogne, Benjamin aut Dabaj, Ivana aut Doummar, Diane aut Fazilleau, Laura aut Ferlini, Alessandra (orcid)0000-0001-8385-9870 aut Gavrilova, Ralitza H. aut Graham, John M. aut Haack, Tobias B. aut Juusola, Jane aut Kant, Sarina G. aut Kayani, Saima aut Keren, Boris aut Ketteler, Petra aut Klöckner, Chiara aut Koopmann, Tamara T. aut Kruisselbrink, Teresa M. aut Kuechler, Alma aut Lambert, Laëtitia aut Latypova, Xénia aut Lebel, Robert Roger aut Leduc, Magalie S. aut Leonardi, Emanuela aut Lewis, Andrea M. aut Liew, Wendy aut Machol, Keren aut Mardini, Samir aut McWalter, Kirsty aut Mignot, Cyril aut McLaughlin, Julie aut Murgia, Alessandra aut Narayanan, Vinodh aut Nava, Caroline aut Neuser, Sonja aut Nizon, Mathilde aut Ognibene, Davide aut Park, Joohyun aut Platzer, Konrad (orcid)0000-0001-6127-6308 aut Poirsier, Céline aut Radtke, Maximilian aut Ramsey, Keri aut Runke, Cassandra K. aut Guillen Sacoto, Maria J. aut Scaglia, Fernando aut Shinawi, Marwan aut Spranger, Stephanie aut Tan, Ee Shien aut Taylor, John aut Trentesaux, Anne-Sophie aut Vairo, Filippo aut Willaert, Rebecca aut Zadeh, Neda aut Urrutia, Raul aut Babovic-Vuksanovic, Dusica aut Zimmermann, Michael T. (orcid)0000-0001-7073-0525 aut Mathie, Alistair (orcid)0000-0001-6094-2890 aut Klee, Eric W. (orcid)0000-0003-2946-5795 aut Enthalten in Genome medicine London : BioMed Central, 2009 14(2022), 1 vom: 13. Juni (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:14 year:2022 number:1 day:13 month:06 https://dx.doi.org/10.1186/s13073-022-01064-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 13 06 |
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10.1186/s13073-022-01064-4 doi (DE-627)SPR050781634 (SPR)s13073-022-01064-4-e DE-627 ger DE-627 rakwb eng Cousin, Margot A. verfasserin (orcid)0000-0002-6119-9346 aut Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 Veale, Emma L. (orcid)0000-0002-6778-9929 aut Dsouza, Nikita R. aut Tripathi, Swarnendu aut Holden, Robyn G. aut Arelin, Maria aut Beek, Geoffrey aut Bekheirnia, Mir Reza aut Beygo, Jasmin aut Bhambhani, Vikas aut Bialer, Martin aut Bigoni, Stefania aut Boelman, Cyrus aut Carmichael, Jenny aut Courtin, Thomas aut Cogne, Benjamin aut Dabaj, Ivana aut Doummar, Diane aut Fazilleau, Laura aut Ferlini, Alessandra (orcid)0000-0001-8385-9870 aut Gavrilova, Ralitza H. aut Graham, John M. aut Haack, Tobias B. aut Juusola, Jane aut Kant, Sarina G. aut Kayani, Saima aut Keren, Boris aut Ketteler, Petra aut Klöckner, Chiara aut Koopmann, Tamara T. aut Kruisselbrink, Teresa M. aut Kuechler, Alma aut Lambert, Laëtitia aut Latypova, Xénia aut Lebel, Robert Roger aut Leduc, Magalie S. aut Leonardi, Emanuela aut Lewis, Andrea M. aut Liew, Wendy aut Machol, Keren aut Mardini, Samir aut McWalter, Kirsty aut Mignot, Cyril aut McLaughlin, Julie aut Murgia, Alessandra aut Narayanan, Vinodh aut Nava, Caroline aut Neuser, Sonja aut Nizon, Mathilde aut Ognibene, Davide aut Park, Joohyun aut Platzer, Konrad (orcid)0000-0001-6127-6308 aut Poirsier, Céline aut Radtke, Maximilian aut Ramsey, Keri aut Runke, Cassandra K. aut Guillen Sacoto, Maria J. aut Scaglia, Fernando aut Shinawi, Marwan aut Spranger, Stephanie aut Tan, Ee Shien aut Taylor, John aut Trentesaux, Anne-Sophie aut Vairo, Filippo aut Willaert, Rebecca aut Zadeh, Neda aut Urrutia, Raul aut Babovic-Vuksanovic, Dusica aut Zimmermann, Michael T. (orcid)0000-0001-7073-0525 aut Mathie, Alistair (orcid)0000-0001-6094-2890 aut Klee, Eric W. (orcid)0000-0003-2946-5795 aut Enthalten in Genome medicine London : BioMed Central, 2009 14(2022), 1 vom: 13. Juni (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:14 year:2022 number:1 day:13 month:06 https://dx.doi.org/10.1186/s13073-022-01064-4 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2022 1 13 06 |
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Cousin, Margot A. @@aut@@ Veale, Emma L. @@aut@@ Dsouza, Nikita R. @@aut@@ Tripathi, Swarnendu @@aut@@ Holden, Robyn G. @@aut@@ Arelin, Maria @@aut@@ Beek, Geoffrey @@aut@@ Bekheirnia, Mir Reza @@aut@@ Beygo, Jasmin @@aut@@ Bhambhani, Vikas @@aut@@ Bialer, Martin @@aut@@ Bigoni, Stefania @@aut@@ Boelman, Cyrus @@aut@@ Carmichael, Jenny @@aut@@ Courtin, Thomas @@aut@@ Cogne, Benjamin @@aut@@ Dabaj, Ivana @@aut@@ Doummar, Diane @@aut@@ Fazilleau, Laura @@aut@@ Ferlini, Alessandra @@aut@@ Gavrilova, Ralitza H. @@aut@@ Graham, John M. @@aut@@ Haack, Tobias B. @@aut@@ Juusola, Jane @@aut@@ Kant, Sarina G. @@aut@@ Kayani, Saima @@aut@@ Keren, Boris @@aut@@ Ketteler, Petra @@aut@@ Klöckner, Chiara @@aut@@ Koopmann, Tamara T. @@aut@@ Kruisselbrink, Teresa M. @@aut@@ Kuechler, Alma @@aut@@ Lambert, Laëtitia @@aut@@ Latypova, Xénia @@aut@@ Lebel, Robert Roger @@aut@@ Leduc, Magalie S. @@aut@@ Leonardi, Emanuela @@aut@@ Lewis, Andrea M. @@aut@@ Liew, Wendy @@aut@@ Machol, Keren @@aut@@ Mardini, Samir @@aut@@ McWalter, Kirsty @@aut@@ Mignot, Cyril @@aut@@ McLaughlin, Julie @@aut@@ Murgia, Alessandra @@aut@@ Narayanan, Vinodh @@aut@@ Nava, Caroline @@aut@@ Neuser, Sonja @@aut@@ Nizon, Mathilde @@aut@@ Ognibene, Davide @@aut@@ Park, Joohyun @@aut@@ Platzer, Konrad @@aut@@ Poirsier, Céline @@aut@@ Radtke, Maximilian @@aut@@ Ramsey, Keri @@aut@@ Runke, Cassandra K. @@aut@@ Guillen Sacoto, Maria J. @@aut@@ Scaglia, Fernando @@aut@@ Shinawi, Marwan @@aut@@ Spranger, Stephanie @@aut@@ Tan, Ee Shien @@aut@@ Taylor, John @@aut@@ Trentesaux, Anne-Sophie @@aut@@ Vairo, Filippo @@aut@@ Willaert, Rebecca @@aut@@ Zadeh, Neda @@aut@@ Urrutia, Raul @@aut@@ Babovic-Vuksanovic, Dusica @@aut@@ Zimmermann, Michael T. @@aut@@ Mathie, Alistair @@aut@@ Klee, Eric W. @@aut@@ |
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Cousin, Margot A. |
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Cousin, Margot A. misc imprinting syndrome misc TASK3 channel misc Neurodevelopmental disorder misc Electrophysiology misc Computational protein modeling Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome imprinting syndrome (dpeaa)DE-He213 TASK3 channel (dpeaa)DE-He213 Neurodevelopmental disorder (dpeaa)DE-He213 Electrophysiology (dpeaa)DE-He213 Computational protein modeling (dpeaa)DE-He213 |
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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
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Cousin, Margot A. |
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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 Bialer, Martin Bigoni, Stefania Boelman, Cyrus Carmichael, Jenny Courtin, Thomas Cogne, Benjamin Dabaj, Ivana Doummar, Diane Fazilleau, Laura Ferlini, Alessandra Gavrilova, Ralitza H. Graham, John M. Haack, Tobias B. Juusola, Jane Kant, Sarina G. Kayani, Saima Keren, Boris Ketteler, Petra Klöckner, Chiara Koopmann, Tamara T. Kruisselbrink, Teresa M. Kuechler, Alma Lambert, Laëtitia Latypova, Xénia Lebel, Robert Roger Leduc, Magalie S. Leonardi, Emanuela Lewis, Andrea M. Liew, Wendy Machol, Keren Mardini, Samir McWalter, Kirsty Mignot, Cyril McLaughlin, Julie Murgia, Alessandra Narayanan, Vinodh Nava, Caroline Neuser, Sonja Nizon, Mathilde Ognibene, Davide Park, Joohyun Platzer, Konrad Poirsier, Céline Radtke, Maximilian Ramsey, Keri Runke, Cassandra K. Guillen Sacoto, Maria J. Scaglia, Fernando Shinawi, Marwan Spranger, Stephanie Tan, Ee Shien Taylor, John Trentesaux, Anne-Sophie Vairo, Filippo Willaert, Rebecca Zadeh, Neda Urrutia, Raul Babovic-Vuksanovic, Dusica Zimmermann, Michael T. Mathie, Alistair Klee, Eric W. |
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Elektronische Aufsätze |
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Cousin, Margot A. |
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10.1186/s13073-022-01064-4 |
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(ORCID)0000-0002-6119-9346 (ORCID)0000-0002-6778-9929 (ORCID)0000-0001-8385-9870 (ORCID)0000-0001-6127-6308 (ORCID)0000-0001-7073-0525 (ORCID)0000-0001-6094-2890 (ORCID)0000-0003-2946-5795 |
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gain and loss of task3 channel function and its regulation by novel variation cause kcnk9 imprinting syndrome |
| title_auth |
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 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. © The Author(s) 2022 |
| abstractGer |
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. © The Author(s) 2022 |
| abstract_unstemmed |
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. © The Author(s) 2022 |
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Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome |
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Veale, Emma L. Dsouza, Nikita R. Tripathi, Swarnendu Holden, Robyn G. Arelin, Maria Beek, Geoffrey Bekheirnia, Mir Reza Beygo, Jasmin Bhambhani, Vikas Bialer, Martin Bigoni, Stefania Boelman, Cyrus Carmichael, Jenny Courtin, Thomas Cogne, Benjamin Dabaj, Ivana Doummar, Diane Fazilleau, Laura Ferlini, Alessandra Gavrilova, Ralitza H. Graham, John M. Haack, Tobias B. Juusola, Jane Kant, Sarina G. Kayani, Saima Keren, Boris Ketteler, Petra Klöckner, Chiara Koopmann, Tamara T. Kruisselbrink, Teresa M. Kuechler, Alma Lambert, Laëtitia Latypova, Xénia Lebel, Robert Roger Leduc, Magalie S. Leonardi, Emanuela Lewis, Andrea M. Liew, Wendy Machol, Keren Mardini, Samir McWalter, Kirsty Mignot, Cyril McLaughlin, Julie Murgia, Alessandra Narayanan, Vinodh Nava, Caroline Neuser, Sonja Nizon, Mathilde Ognibene, Davide Park, Joohyun Platzer, Konrad Poirsier, Céline Radtke, Maximilian Ramsey, Keri Runke, Cassandra K. Guillen Sacoto, Maria J. Scaglia, Fernando Shinawi, Marwan Spranger, Stephanie Tan, Ee Shien Taylor, John Trentesaux, Anne-Sophie Vairo, Filippo Willaert, Rebecca Zadeh, Neda Urrutia, Raul Babovic-Vuksanovic, Dusica Zimmermann, Michael T. Mathie, Alistair Klee, Eric W. |
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Veale, Emma L. Dsouza, Nikita R. Tripathi, Swarnendu Holden, Robyn G. Arelin, Maria Beek, Geoffrey Bekheirnia, Mir Reza Beygo, Jasmin Bhambhani, Vikas Bialer, Martin Bigoni, Stefania Boelman, Cyrus Carmichael, Jenny Courtin, Thomas Cogne, Benjamin Dabaj, Ivana Doummar, Diane Fazilleau, Laura Ferlini, Alessandra Gavrilova, Ralitza H. Graham, John M. Haack, Tobias B. Juusola, Jane Kant, Sarina G. Kayani, Saima Keren, Boris Ketteler, Petra Klöckner, Chiara Koopmann, Tamara T. Kruisselbrink, Teresa M. Kuechler, Alma Lambert, Laëtitia Latypova, Xénia Lebel, Robert Roger Leduc, Magalie S. Leonardi, Emanuela Lewis, Andrea M. Liew, Wendy Machol, Keren Mardini, Samir McWalter, Kirsty Mignot, Cyril McLaughlin, Julie Murgia, Alessandra Narayanan, Vinodh Nava, Caroline Neuser, Sonja Nizon, Mathilde Ognibene, Davide Park, Joohyun Platzer, Konrad Poirsier, Céline Radtke, Maximilian Ramsey, Keri Runke, Cassandra K. Guillen Sacoto, Maria J. Scaglia, Fernando Shinawi, Marwan Spranger, Stephanie Tan, Ee Shien Taylor, John Trentesaux, Anne-Sophie Vairo, Filippo Willaert, Rebecca Zadeh, Neda Urrutia, Raul Babovic-Vuksanovic, Dusica Zimmermann, Michael T. Mathie, Alistair Klee, Eric W. |
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| score |
7.3987913 |