Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Christiane K Bauer; Paolo Calligari; Francesca Clementina Radio; Viviana Caputo; Maria Lisa Dentici; Nadia Falah; Frances High; Francesca Pantaleoni; Sabina Barresi; Andrea Ciolfi; Simone Pizzi; Alessandro Bruselles; Richard Person; Sarah Richards; Megan T Cho; Daniela J Claps Sepulveda; Stefano Pro; Roberta Battini; Giuseppe Zampino; Maria Cristina Digilio; Gianfranco Bocchinfuso; Bruno Dallapiccola; Lorenzo Stella; Marco Tartaglia

doi:10.1016/j.ajhg.2018.09.001

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Standard

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. / Bauer, Christiane K; Calligari, Paolo; Radio, Francesca Clementina; Caputo, Viviana; Dentici, Maria Lisa; Falah, Nadia; High, Frances; Pantaleoni, Francesca; Barresi, Sabina; Ciolfi, Andrea; Pizzi, Simone; Bruselles, Alessandro; Person, Richard; Richards, Sarah; Cho, Megan T; Claps Sepulveda, Daniela J; Pro, Stefano; Battini, Roberta; Zampino, Giuseppe; Digilio, Maria Cristina; Bocchinfuso, Gianfranco; Dallapiccola, Bruno; Stella, Lorenzo; Tartaglia, Marco.

in: AM J HUM GENET, Jahrgang 103, Nr. 4, 04.10.2018, S. 621-630.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Bauer, CK, Calligari, P, Radio, FC, Caputo, V, Dentici, ML, Falah, N, High, F, Pantaleoni, F, Barresi, S, Ciolfi, A, Pizzi, S, Bruselles, A, Person, R, Richards, S, Cho, MT, Claps Sepulveda, DJ, Pro, S, Battini, R, Zampino, G, Digilio, MC, Bocchinfuso, G, Dallapiccola, B, Stella, L & Tartaglia, M 2018, 'Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome', AM J HUM GENET, Jg. 103, Nr. 4, S. 621-630. https://doi.org/10.1016/j.ajhg.2018.09.001

APA

Bauer, C. K., Calligari, P., Radio, F. C., Caputo, V., Dentici, M. L., Falah, N., High, F., Pantaleoni, F., Barresi, S., Ciolfi, A., Pizzi, S., Bruselles, A., Person, R., Richards, S., Cho, M. T., Claps Sepulveda, D. J., Pro, S., Battini, R., Zampino, G., ... Tartaglia, M. (2018). Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. AM J HUM GENET, 103(4), 621-630. https://doi.org/10.1016/j.ajhg.2018.09.001

Vancouver

Bauer CK, Calligari P, Radio FC, Caputo V, Dentici ML, Falah N et al. Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. AM J HUM GENET. 2018 Okt 4;103(4):621-630. https://doi.org/10.1016/j.ajhg.2018.09.001

Bibtex

@article{6f08b981d20a4658b627f289b47405f2,

title = "Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome",

abstract = "Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.",

keywords = "Journal Article",

author = "Bauer, {Christiane K} and Paolo Calligari and Radio, {Francesca Clementina} and Viviana Caputo and Dentici, {Maria Lisa} and Nadia Falah and Frances High and Francesca Pantaleoni and Sabina Barresi and Andrea Ciolfi and Simone Pizzi and Alessandro Bruselles and Richard Person and Sarah Richards and Cho, {Megan T} and {Claps Sepulveda}, {Daniela J} and Stefano Pro and Roberta Battini and Giuseppe Zampino and Digilio, {Maria Cristina} and Gianfranco Bocchinfuso and Bruno Dallapiccola and Lorenzo Stella and Marco Tartaglia",

year = "2018",

month = oct,

day = "4",

doi = "10.1016/j.ajhg.2018.09.001",

language = "English",

volume = "103",

pages = "621--630",

journal = "AM J HUM GENET",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

RIS

TY - JOUR

T1 - Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

AU - Bauer, Christiane K

AU - Calligari, Paolo

AU - Radio, Francesca Clementina

AU - Caputo, Viviana

AU - Dentici, Maria Lisa

AU - Falah, Nadia

AU - High, Frances

AU - Pantaleoni, Francesca

AU - Barresi, Sabina

AU - Ciolfi, Andrea

AU - Pizzi, Simone

AU - Bruselles, Alessandro

AU - Person, Richard

AU - Richards, Sarah

AU - Cho, Megan T

AU - Claps Sepulveda, Daniela J

AU - Pro, Stefano

AU - Battini, Roberta

AU - Zampino, Giuseppe

AU - Digilio, Maria Cristina

AU - Bocchinfuso, Gianfranco

AU - Dallapiccola, Bruno

AU - Stella, Lorenzo

AU - Tartaglia, Marco

PY - 2018/10/4

Y1 - 2018/10/4

N2 - Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.

AB - Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.

KW - Journal Article

U2 - 10.1016/j.ajhg.2018.09.001

DO - 10.1016/j.ajhg.2018.09.001

M3 - SCORING: Journal article

C2 - 30290154

VL - 103

SP - 621

EP - 630

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 4

ER -