Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

C.K. Bauer, P. Calligari, F.C. Radio, V. Caputo, M.L. Dentici, N. Falah, F. High, F. Pantaleoni, S. Barresi, A. Ciolfi, S. Pizzi, A. Bruselles, R. Person, S. Richards, M.T. Cho, D.J. Claps Sepulveda, S. Pro, R. Battini, G. Zampino, M.C. Digilio & 4 others G. Bocchinfuso, B. Dallapiccola, L. Stella, M. Tartaglia

Research output: Contribution to journalArticle

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. © 2018 American Society of Human Genetics
Original languageEnglish
Pages (from-to)621-630
Number of pages10
JournalAmerican Journal of Human Genetics
Volume103
Issue number4
DOIs
Publication statusPublished - 2018

Fingerprint

Arachidonic Acid
Mutation
Gingival Overgrowth
Missense Mutation
Molecular Dynamics Simulation
Plasma Cells
Ion Channels
Synaptic Transmission
Intellectual Disability
Membrane Potentials
Cardiac Arrhythmias
Epilepsy
Potassium
Cell Membrane
Lipids

Keywords

  • channelopathy
  • epilepsy
  • FHEIG syndrome
  • gingival overgrowth
  • hypertrichosis
  • intellectual disability
  • K2P channels
  • neurodevelopmental disorder
  • TRAAK
  • alanine
  • arachidonic acid
  • complementary DNA
  • glutamine
  • polyunsaturated fatty acid
  • proline
  • amino acid substitution
  • Article
  • case report
  • cell adhesion
  • channel gating
  • child
  • clinical article
  • clinical feature
  • conformational transition
  • developmental delay
  • DNA determination
  • face dysmorphia
  • facies
  • female
  • gain of function mutation
  • gene location
  • genetic variability
  • gestalt psychology
  • gingiva overgrowth
  • human
  • infant
  • intellectual impairment
  • KCNK4 gene
  • male
  • mechanical stimulation
  • membrane potential
  • missense mutation
  • molecular dynamics
  • mutational analysis
  • patch clamp technique
  • pleiotropy
  • point mutation
  • preschool child
  • priority journal
  • protein function
  • Sanger sequencing
  • school child
  • sensitivity analysis
  • whole exome sequencing

Cite this

Bauer, C. K., Calligari, P., Radio, F. C., Caputo, V., Dentici, M. L., Falah, N., ... Tartaglia, M. (2018). Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. American Journal of Human Genetics, 103(4), 621-630. https://doi.org/10.1016/j.ajhg.2018.09.001

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. / 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.; Digilio, M.C.; Bocchinfuso, G.; Dallapiccola, B.; Stella, L.; Tartaglia, M.

In: American Journal of Human Genetics, Vol. 103, No. 4, 2018, p. 621-630.

Research output: Contribution to journalArticle

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', American Journal of Human Genetics, vol. 103, no. 4, pp. 621-630. https://doi.org/10.1016/j.ajhg.2018.09.001
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. ; Digilio, M.C. ; Bocchinfuso, G. ; Dallapiccola, B. ; Stella, L. ; Tartaglia, M. / Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome. In: American Journal of Human Genetics. 2018 ; Vol. 103, No. 4. pp. 621-630.
@article{a3ed5bd70ec04e13a1c87c51c5f4be9b,
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. {\circledC} 2018 American Society of Human Genetics",
keywords = "channelopathy, epilepsy, FHEIG syndrome, gingival overgrowth, hypertrichosis, intellectual disability, K2P channels, neurodevelopmental disorder, TRAAK, alanine, arachidonic acid, complementary DNA, glutamine, polyunsaturated fatty acid, proline, amino acid substitution, Article, case report, cell adhesion, channel gating, child, clinical article, clinical feature, conformational transition, developmental delay, DNA determination, face dysmorphia, facies, female, gain of function mutation, gene location, genetic variability, gestalt psychology, gingiva overgrowth, human, infant, intellectual impairment, KCNK4 gene, male, mechanical stimulation, membrane potential, missense mutation, molecular dynamics, mutational analysis, patch clamp technique, pleiotropy, point mutation, preschool child, priority journal, protein function, Sanger sequencing, school child, sensitivity analysis, whole exome sequencing",
author = "C.K. Bauer and P. Calligari and F.C. Radio and V. Caputo and M.L. Dentici and N. Falah and F. High and F. Pantaleoni and S. Barresi and A. Ciolfi and S. Pizzi and A. Bruselles and R. Person and S. Richards and M.T. Cho and {Claps Sepulveda}, D.J. and S. Pro and R. Battini and G. Zampino and M.C. Digilio and G. Bocchinfuso and B. Dallapiccola and L. Stella and M. Tartaglia",
note = "Cited By :1 Export Date: 11 April 2019 CODEN: AJHGA Correspondence Address: Bauer, C.K.; Center for Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-EppendorfGermany; email: cbauer@uke.uni-hamburg.de Chemicals/CAS: alanine, 56-41-7, 6898-94-8; arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; glutamine, 56-85-9, 6899-04-3; proline, 147-85-3, 7005-20-1 Funding details: Partnership for Advanced Computing in Europe AISBL, 2017174118 Funding text 1: The authors wish to thank the participating families; Thomas Baukrowitz (Institute of Physiology, Kiel University, Kiel) for providing the KCNK4 cDNA; Fanny Kort{\"u}m, Frederike L. Harms, and Inka Jantke (Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg) for generating KCNK4 expression constructs; and Serenella Venanzi (Istituto Superiore di Sanit{\`a}, Rome) and Annett Hasse (Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg) for technical support. This work was supported, in part, by Fondazione Bambino Ges{\`u} (Vite Coraggiose to B.D. and M.T.) and the Italian Ministry of Health (Ricerca Corrente 2017 and 2018 to M.L.D., M.C.D., A.C., and M.T.). G.B. acknowledges PRACE (Partnership for Advanced Computing in Europe , grant 2017174118 ), and M.T. and G.B. acknowledge CINECA for the computational resources. References: Hille, B., Ion channels of excitable membranes (2001), Sinauer Associates; Tian, C., Zhu, R., Zhu, L., Qiu, T., Cao, Z., Kang, T., Potassium channels: structures, diseases, and modulators (2014) Chem. Biol. Drug Des., 83, pp. 1-26; Urrego, D., Tomczak, A.P., Zahed, F., St{\"u}hmer, W., Pardo, L.A., Potassium channels in cell cycle and cell proliferation (2014) Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, p. 20130094; Shieh, C.C., Coghlan, M., Sullivan, J.P., Gopalakrishnan, M., Potassium channels: molecular defects, diseases, and therapeutic opportunities (2000) Pharmacol. Rev., 52, pp. 557-594; Jentsch, T.J., Neuronal KCNQ potassium channels: physiology and role in disease (2000) Nat. Rev. Neurosci., 1, pp. 21-30; Chiamvimonvat, N., Chen-Izu, Y., Clancy, C.E., Deschenes, I., Dobrev, D., Heijman, J., Izu, L., Vandenberg, J.I., Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics (2017) J. Physiol., 595, pp. 2229-2252; Bockenhauer, D., Feather, S., Stanescu, H.C., Bandulik, S., Zdebik, A.A., Reichold, M., Tobin, J., Landoure, G., Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations (2009) N. Engl. J. Med., 360, pp. 1960-1970; Simons, C., Rash, L.D., Crawford, J., Ma, L., Cristofori-Armstrong, B., Miller, D., Ru, K., Jacquinet, A., Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy (2015) Nat. Genet., 47, pp. 73-77; Kort{\"u}m, F., Caputo, V., Bauer, C.K., Stella, L., Ciolfi, A., Alawi, M., Bocchinfuso, G., Dentici, M.L., Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome (2015) Nat. Genet., 47, pp. 661-667; Harakalova, M., van Harssel, J.J., Terhal, P.A., van Lieshout, S., Duran, K., Renkens, I., Amor, D.J., Turner, C.L., Dominant missense mutations in ABCC9 cause Cant{\'u} syndrome (2012) Nat. Genet., 44, pp. 793-796; Cooper, P.E., Reutter, H., Woelfle, J., Engels, H., Grange, D.K., van Haaften, G., van Bon, B.W., Nichols, C.G., Cant{\'u} syndrome resulting from activating mutation in the KCNJ8 gene (2014) Hum. Mutat., 35, pp. 809-813; Fink, M., Lesage, F., Duprat, F., Heurteaux, C., Reyes, R., Fosset, M., Lazdunski, M., A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids (1998) EMBO J., 17, pp. 3297-3308; Feliciangeli, S., Chatelain, F.C., Bichet, D., Lesage, F., The family of K2P channels: salient structural and functional properties (2015) J. Physiol., 593, pp. 2587-2603; Sep{\'u}lveda, F.V., Pablo Cid, L., Teulon, J., Niemeyer, M.I., Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels (2015) Physiol. Rev., 95, pp. 179-217; Niceta, M., Stellacci, E., Gripp, K.W., Zampino, G., Kousi, M., Anselmi, M., Traversa, A., Bruselles, A., Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a Down syndrome-like facies (2015) Am. J. Hum. 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year = "2018",
doi = "10.1016/j.ajhg.2018.09.001",
language = "English",
volume = "103",
pages = "621--630",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

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

AU - Bauer, C.K.

AU - Calligari, P.

AU - Radio, F.C.

AU - Caputo, V.

AU - Dentici, M.L.

AU - Falah, N.

AU - High, F.

AU - Pantaleoni, F.

AU - Barresi, S.

AU - Ciolfi, A.

AU - Pizzi, S.

AU - Bruselles, A.

AU - Person, R.

AU - Richards, S.

AU - Cho, M.T.

AU - Claps Sepulveda, D.J.

AU - Pro, S.

AU - Battini, R.

AU - Zampino, G.

AU - Digilio, M.C.

AU - Bocchinfuso, G.

AU - Dallapiccola, B.

AU - Stella, L.

AU - Tartaglia, M.

N1 - Cited By :1 Export Date: 11 April 2019 CODEN: AJHGA Correspondence Address: Bauer, C.K.; Center for Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-EppendorfGermany; email: cbauer@uke.uni-hamburg.de Chemicals/CAS: alanine, 56-41-7, 6898-94-8; arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; glutamine, 56-85-9, 6899-04-3; proline, 147-85-3, 7005-20-1 Funding details: Partnership for Advanced Computing in Europe AISBL, 2017174118 Funding text 1: The authors wish to thank the participating families; Thomas Baukrowitz (Institute of Physiology, Kiel University, Kiel) for providing the KCNK4 cDNA; Fanny Kortüm, Frederike L. Harms, and Inka Jantke (Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg) for generating KCNK4 expression constructs; and Serenella Venanzi (Istituto Superiore di Sanità, Rome) and Annett Hasse (Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg) for technical support. This work was supported, in part, by Fondazione Bambino Gesù (Vite Coraggiose to B.D. and M.T.) and the Italian Ministry of Health (Ricerca Corrente 2017 and 2018 to M.L.D., M.C.D., A.C., and M.T.). G.B. acknowledges PRACE (Partnership for Advanced Computing in Europe , grant 2017174118 ), and M.T. and G.B. acknowledge CINECA for the computational resources. References: Hille, B., Ion channels of excitable membranes (2001), Sinauer Associates; Tian, C., Zhu, R., Zhu, L., Qiu, T., Cao, Z., Kang, T., Potassium channels: structures, diseases, and modulators (2014) Chem. Biol. Drug Des., 83, pp. 1-26; Urrego, D., Tomczak, A.P., Zahed, F., Stühmer, W., Pardo, L.A., Potassium channels in cell cycle and cell proliferation (2014) Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, p. 20130094; Shieh, C.C., Coghlan, M., Sullivan, J.P., Gopalakrishnan, M., Potassium channels: molecular defects, diseases, and therapeutic opportunities (2000) Pharmacol. Rev., 52, pp. 557-594; Jentsch, T.J., Neuronal KCNQ potassium channels: physiology and role in disease (2000) Nat. Rev. Neurosci., 1, pp. 21-30; Chiamvimonvat, N., Chen-Izu, Y., Clancy, C.E., Deschenes, I., Dobrev, D., Heijman, J., Izu, L., Vandenberg, J.I., Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics (2017) J. Physiol., 595, pp. 2229-2252; Bockenhauer, D., Feather, S., Stanescu, H.C., Bandulik, S., Zdebik, A.A., Reichold, M., Tobin, J., Landoure, G., Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations (2009) N. Engl. J. Med., 360, pp. 1960-1970; Simons, C., Rash, L.D., Crawford, J., Ma, L., Cristofori-Armstrong, B., Miller, D., Ru, K., Jacquinet, A., Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy (2015) Nat. Genet., 47, pp. 73-77; Kortüm, F., Caputo, V., Bauer, C.K., Stella, L., Ciolfi, A., Alawi, M., Bocchinfuso, G., Dentici, M.L., Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome (2015) Nat. Genet., 47, pp. 661-667; Harakalova, M., van Harssel, J.J., Terhal, P.A., van Lieshout, S., Duran, K., Renkens, I., Amor, D.J., Turner, C.L., Dominant missense mutations in ABCC9 cause Cantú syndrome (2012) Nat. Genet., 44, pp. 793-796; Cooper, P.E., Reutter, H., Woelfle, J., Engels, H., Grange, D.K., van Haaften, G., van Bon, B.W., Nichols, C.G., Cantú syndrome resulting from activating mutation in the KCNJ8 gene (2014) Hum. Mutat., 35, pp. 809-813; Fink, M., Lesage, F., Duprat, F., Heurteaux, C., Reyes, R., Fosset, M., Lazdunski, M., A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids (1998) EMBO J., 17, pp. 3297-3308; Feliciangeli, S., Chatelain, F.C., Bichet, D., Lesage, F., The family of K2P channels: salient structural and functional properties (2015) J. Physiol., 593, pp. 2587-2603; Sepúlveda, F.V., Pablo Cid, L., Teulon, J., Niemeyer, M.I., Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels (2015) Physiol. Rev., 95, pp. 179-217; Niceta, M., Stellacci, E., Gripp, K.W., Zampino, G., Kousi, M., Anselmi, M., Traversa, A., Bruselles, A., Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a Down syndrome-like facies (2015) Am. J. Hum. 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PY - 2018

Y1 - 2018

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. © 2018 American Society of Human Genetics

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. © 2018 American Society of Human Genetics

KW - channelopathy

KW - epilepsy

KW - FHEIG syndrome

KW - gingival overgrowth

KW - hypertrichosis

KW - intellectual disability

KW - K2P channels

KW - neurodevelopmental disorder

KW - TRAAK

KW - alanine

KW - arachidonic acid

KW - complementary DNA

KW - glutamine

KW - polyunsaturated fatty acid

KW - proline

KW - amino acid substitution

KW - Article

KW - case report

KW - cell adhesion

KW - channel gating

KW - child

KW - clinical article

KW - clinical feature

KW - conformational transition

KW - developmental delay

KW - DNA determination

KW - face dysmorphia

KW - facies

KW - female

KW - gain of function mutation

KW - gene location

KW - genetic variability

KW - gestalt psychology

KW - gingiva overgrowth

KW - human

KW - infant

KW - intellectual impairment

KW - KCNK4 gene

KW - male

KW - mechanical stimulation

KW - membrane potential

KW - missense mutation

KW - molecular dynamics

KW - mutational analysis

KW - patch clamp technique

KW - pleiotropy

KW - point mutation

KW - preschool child

KW - priority journal

KW - protein function

KW - Sanger sequencing

KW - school child

KW - sensitivity analysis

KW - whole exome sequencing

U2 - 10.1016/j.ajhg.2018.09.001

DO - 10.1016/j.ajhg.2018.09.001

M3 - Article

VL - 103

SP - 621

EP - 630

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -