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 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

doi:10.1186/s13073-022-01064-4

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	62
Journal	Genome medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13073-022-01064-4
State	Published - Dec 2022

Keywords

Computational protein modeling
Electrophysiology
KCNK9 imprinting syndrome
Neurodevelopmental disorder
TASK3 channel

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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10.1186/s13073-022-01064-4

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Cousin, M. A., Veale, E. L., Dsouza, N. R., Tripathi, S., Holden, R. G., Arelin, M., Beek, G., Bekheirnia, M. R., Beygo, J., Bhambhani, V., Bialer, M., Bigoni, S., Boelman, C., Carmichael, J., Courtin, T., Cogne, B., Dabaj, I., Doummar, D., Fazilleau, L., ... Klee, E. W. (2022). Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. Genome medicine, 14(1), Article 62. https://doi.org/10.1186/s13073-022-01064-4

Cousin, MA, Veale, EL, Dsouza, NR, Tripathi, S, Holden, RG, Arelin, M, Beek, G, Bekheirnia, MR, Beygo, J, Bhambhani, V, Bialer, M, Bigoni, S, Boelman, C, Carmichael, J, Courtin, T, Cogne, B, Dabaj, I, Doummar, D, Fazilleau, L, Ferlini, A, Gavrilova, RH, Graham, JM, Haack, TB, Juusola, J, Kant, SG, Kayani, S, Keren, B, Ketteler, P, Klöckner, C, Koopmann, TT, Kruisselbrink, TM, Kuechler, A, Lambert, L, Latypova, X, Lebel, RR, Leduc, MS, Leonardi, E, Lewis, AM, Liew, W, Machol, K, Mardini, S, McWalter, K, Mignot, C, McLaughlin, J, Murgia, A, Narayanan, V, Nava, C, Neuser, S, Nizon, M, Ognibene, D, Park, J, Platzer, K, Poirsier, C, Radtke, M, Ramsey, K, Runke, CK, Guillen Sacoto, MJ, Scaglia, F, Shinawi, M, Spranger, S, Tan, ES, Taylor, J, Trentesaux, AS, Vairo, F, Willaert, R, Zadeh, N, Urrutia, R, Babovic-Vuksanovic, D, Zimmermann, MT, Mathie, A & Klee, EW 2022, 'Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome', Genome medicine, vol. 14, no. 1, 62. https://doi.org/10.1186/s13073-022-01064-4

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title = "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.",

keywords = "Computational protein modeling, Electrophysiology, KCNK9 imprinting syndrome, Neurodevelopmental disorder, TASK3 channel",

author = "Cousin, {Margot A.} and Veale, {Emma L.} and Dsouza, {Nikita R.} and Swarnendu Tripathi and Holden, {Robyn G.} and Maria Arelin and Geoffrey Beek and Bekheirnia, {Mir Reza} and Jasmin Beygo and Vikas Bhambhani and Martin Bialer and Stefania Bigoni and Cyrus Boelman and Jenny Carmichael and Thomas Courtin and Benjamin Cogne and Ivana Dabaj and Diane Doummar and Laura Fazilleau and Alessandra Ferlini and Gavrilova, {Ralitza H.} and Graham, {John M.} and Haack, {Tobias B.} and Jane Juusola and Kant, {Sarina G.} and Saima Kayani and Boris Keren and Petra Ketteler and Chiara Kl{\"o}ckner and Koopmann, {Tamara T.} and Kruisselbrink, {Teresa M.} and Alma Kuechler and La{\"e}titia Lambert and X{\'e}nia Latypova and Lebel, {Robert Roger} and Leduc, {Magalie S.} and Emanuela Leonardi and Lewis, {Andrea M.} and Wendy Liew and Keren Machol and Samir Mardini and Kirsty McWalter and Cyril Mignot and Julie McLaughlin and Alessandra Murgia and Vinodh Narayanan and Caroline Nava and Sonja Neuser and Mathilde Nizon and Davide Ognibene and Joohyun Park and Konrad Platzer and C{\'e}line Poirsier and Maximilian Radtke and Keri Ramsey and Runke, {Cassandra K.} and {Guillen Sacoto}, {Maria J.} and Fernando Scaglia and Marwan Shinawi and Stephanie Spranger and Tan, {Ee Shien} and John Taylor and Trentesaux, {Anne Sophie} and Filippo Vairo and Rebecca Willaert and Neda Zadeh and Raul Urrutia and Dusica Babovic-Vuksanovic and Zimmermann, {Michael T.} and Alistair Mathie and Klee, {Eric W.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13073-022-01064-4",

language = "English (US)",

volume = "14",

journal = "Genome medicine",

issn = "1756-994X",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

AU - Cousin, Margot A.

AU - Veale, Emma L.

AU - Dsouza, Nikita R.

AU - Tripathi, Swarnendu

AU - Holden, Robyn G.

AU - Arelin, Maria

AU - Beek, Geoffrey

AU - Bekheirnia, Mir Reza

AU - Beygo, Jasmin

AU - Bhambhani, Vikas

AU - Bialer, Martin

AU - Bigoni, Stefania

AU - Boelman, Cyrus

AU - Carmichael, Jenny

AU - Courtin, Thomas

AU - Cogne, Benjamin

AU - Dabaj, Ivana

AU - Doummar, Diane

AU - Fazilleau, Laura

AU - Ferlini, Alessandra

AU - Gavrilova, Ralitza H.

AU - Graham, John M.

AU - Haack, Tobias B.

AU - Juusola, Jane

AU - Kant, Sarina G.

AU - Kayani, Saima

AU - Keren, Boris

AU - Ketteler, Petra

AU - Klöckner, Chiara

AU - Koopmann, Tamara T.

AU - Kruisselbrink, Teresa M.

AU - Kuechler, Alma

AU - Lambert, Laëtitia

AU - Latypova, Xénia

AU - Lebel, Robert Roger

AU - Leduc, Magalie S.

AU - Leonardi, Emanuela

AU - Lewis, Andrea M.

AU - Liew, Wendy

AU - Machol, Keren

AU - Mardini, Samir

AU - McWalter, Kirsty

AU - Mignot, Cyril

AU - McLaughlin, Julie

AU - Murgia, Alessandra

AU - Narayanan, Vinodh

AU - Nava, Caroline

AU - Neuser, Sonja

AU - Nizon, Mathilde

AU - Ognibene, Davide

AU - Park, Joohyun

AU - Platzer, Konrad

AU - Poirsier, Céline

AU - Radtke, Maximilian

AU - Ramsey, Keri

AU - Runke, Cassandra K.

AU - Guillen Sacoto, Maria J.

AU - Scaglia, Fernando

AU - Shinawi, Marwan

AU - Spranger, Stephanie

AU - Tan, Ee Shien

AU - Taylor, John

AU - Trentesaux, Anne Sophie

AU - Vairo, Filippo

AU - Willaert, Rebecca

AU - Zadeh, Neda

AU - Urrutia, Raul

AU - Babovic-Vuksanovic, Dusica

AU - Zimmermann, Michael T.

AU - Mathie, Alistair

AU - Klee, Eric W.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Computational protein modeling

KW - Electrophysiology

KW - KCNK9 imprinting syndrome

KW - Neurodevelopmental disorder

KW - TASK3 channel

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UR - http://www.scopus.com/inward/citedby.url?scp=85131795908&partnerID=8YFLogxK

U2 - 10.1186/s13073-022-01064-4

DO - 10.1186/s13073-022-01064-4

M3 - Article

C2 - 35698242

AN - SCOPUS:85131795908

SN - 1756-994X

VL - 14

JO - Genome medicine

JF - Genome medicine

IS - 1

M1 - 62

ER -

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

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