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17-06-2024 | Epilepsy | Original Article

Novel KCNQ2 missense variant expands the genotype spectrum of DEE7

Authors: Chao Wang, JinXia Zhai, YongJun Chen

Published in: Neurological Sciences

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Abstract

Background

KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences.

Methods

In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient.

Results

A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities.

Conclusion

Our findings expands the genetic profile of KCNQ2 and enhances the genotype – phenotype link.
Literature
1.
go back to reference Hawkins NA, Anderson LL, Gertler TS, Laux L, George AL, Kearney JA (2017) Screening of conventional anticonvulsants in a genetic mouse model of epilepsy. Ann Clin Transl Neurol 4(5):326–339CrossRefPubMedPubMedCentral Hawkins NA, Anderson LL, Gertler TS, Laux L, George AL, Kearney JA (2017) Screening of conventional anticonvulsants in a genetic mouse model of epilepsy. Ann Clin Transl Neurol 4(5):326–339CrossRefPubMedPubMedCentral
2.
go back to reference Contreras Ramirez V, Vaddiparti A, Blumenfeld H (2022) Testing awareness in focal seizures: Clinical practice and interpretation of current guidelines. Ann Clin Transl Neurol 9(5):762–765CrossRefPubMedPubMedCentral Contreras Ramirez V, Vaddiparti A, Blumenfeld H (2022) Testing awareness in focal seizures: Clinical practice and interpretation of current guidelines. Ann Clin Transl Neurol 9(5):762–765CrossRefPubMedPubMedCentral
3.
go back to reference Vongerichten AN, Santos GSD, Aristovich K, Avery J, McEvoy A, Walker M, Holder DS (2016) Characterisation and imaging of cortical impedance changes during interictal and ictal activity in the anaesthetised rat. Neuroimage 124(Pt A):813–823CrossRefPubMed Vongerichten AN, Santos GSD, Aristovich K, Avery J, McEvoy A, Walker M, Holder DS (2016) Characterisation and imaging of cortical impedance changes during interictal and ictal activity in the anaesthetised rat. Neuroimage 124(Pt A):813–823CrossRefPubMed
4.
go back to reference Amadori E, Scala M, Cereda GS, Vari MS, Marchese F, Di Pisa V, Mancardi MM, Giacomini T, Siri L, Vercellino F et al (2020) Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the “beyond epilepsy” project. Ital J Pediatr 46(1):92CrossRefPubMedPubMedCentral Amadori E, Scala M, Cereda GS, Vari MS, Marchese F, Di Pisa V, Mancardi MM, Giacomini T, Siri L, Vercellino F et al (2020) Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the “beyond epilepsy” project. Ital J Pediatr 46(1):92CrossRefPubMedPubMedCentral
5.
go back to reference Scala M, Bianchi A, Bisulli F, Coppola A, Elia M, Trivisano M, Pruna D, Pippucci T, Canafoglia L, Lattanzi S et al (2020) Advances in genetic testing and optimization of clinical management in children and adults with epilepsy. Expert Rev Neurother 20(3):251–269CrossRefPubMed Scala M, Bianchi A, Bisulli F, Coppola A, Elia M, Trivisano M, Pruna D, Pippucci T, Canafoglia L, Lattanzi S et al (2020) Advances in genetic testing and optimization of clinical management in children and adults with epilepsy. Expert Rev Neurother 20(3):251–269CrossRefPubMed
6.
go back to reference Cheng Z, Zhou H, Sherva R, Farrer LA, Kranzler HR, Gelernter J (2018) Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biol Psychiatry 84(10):762–770CrossRefPubMedPubMedCentral Cheng Z, Zhou H, Sherva R, Farrer LA, Kranzler HR, Gelernter J (2018) Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. Biol Psychiatry 84(10):762–770CrossRefPubMedPubMedCentral
7.
go back to reference Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Bentley AR, Shriner D et al (2019) ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. Nat Commun 10(1):3195CrossRefPubMedPubMedCentral Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Bentley AR, Shriner D et al (2019) ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. Nat Commun 10(1):3195CrossRefPubMedPubMedCentral
9.
go back to reference Yue JF, Qiao GH, Liu N, Nan FJ, Gao ZB (2016) Novel KCNQ2 channel activators discovered using fluorescence-based and automated patch-clamp-based high-throughput screening techniques. Acta Pharmacol Sin 37(1):105–110CrossRefPubMedPubMedCentral Yue JF, Qiao GH, Liu N, Nan FJ, Gao ZB (2016) Novel KCNQ2 channel activators discovered using fluorescence-based and automated patch-clamp-based high-throughput screening techniques. Acta Pharmacol Sin 37(1):105–110CrossRefPubMedPubMedCentral
10.
go back to reference Nabbout R, Dulac O (2012) Epilepsy. Genetics of early-onset epilepsy with encephalopathy. Nat Rev Neurol 8(3):129–130CrossRefPubMed Nabbout R, Dulac O (2012) Epilepsy. Genetics of early-onset epilepsy with encephalopathy. Nat Rev Neurol 8(3):129–130CrossRefPubMed
11.
go back to reference Li P, Chen Z, Xu H, Sun H, Li H, Liu H, Yang H, Gao Z, Jiang H, Li M (2013) The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands. Cell Res 23(9):1106–1118CrossRefPubMedPubMedCentral Li P, Chen Z, Xu H, Sun H, Li H, Liu H, Yang H, Gao Z, Jiang H, Li M (2013) The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands. Cell Res 23(9):1106–1118CrossRefPubMedPubMedCentral
12.
go back to reference Scott RC, Holmes GL (2012) Before epilepsy unfolds: opening up the potassium door in neonatal seizures. Nat Med 18(11):1624–1625CrossRefPubMed Scott RC, Holmes GL (2012) Before epilepsy unfolds: opening up the potassium door in neonatal seizures. Nat Med 18(11):1624–1625CrossRefPubMed
13.
go back to reference Bayat A, Iavarone S, Miceli F, Jakobsen AV, Johannesen KM, Nikanorova M, Ploski R, Szymanska K, Flamini R, Cooper EC et al (2023) Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment. Neurotherapeutics 21(1):e00296CrossRefPubMedPubMedCentral Bayat A, Iavarone S, Miceli F, Jakobsen AV, Johannesen KM, Nikanorova M, Ploski R, Szymanska K, Flamini R, Cooper EC et al (2023) Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment. Neurotherapeutics 21(1):e00296CrossRefPubMedPubMedCentral
14.
go back to reference Zhang Y, Xue Y, Ma Y, Du X, Lu B, Wang Y, Yan Z (2024) Improved classification and pathogenicity assessment by comprehensive functional studies in a large data set of KCNQ2 variants. Life Sci 339:122378 Zhang Y, Xue Y, Ma Y, Du X, Lu B, Wang Y, Yan Z (2024) Improved classification and pathogenicity assessment by comprehensive functional studies in a large data set of KCNQ2 variants. Life Sci 339:122378
15.
go back to reference Mendoza RP, Doytcheva K, Ud Dean M, Jorgenson KM, Choi D, Segal J, Wang P, Lastra RR (2024) Whole exome sequencing of placental chorangioma. Placenta 149:13–17CrossRefPubMed Mendoza RP, Doytcheva K, Ud Dean M, Jorgenson KM, Choi D, Segal J, Wang P, Lastra RR (2024) Whole exome sequencing of placental chorangioma. Placenta 149:13–17CrossRefPubMed
16.
go back to reference Li D, Li S, Zhou J, Zheng L, Liu G, Ding C, Yuan X (2023) Case Report: Identification of a rare nonsense mutation in the POC1A gene by NGS in a diabetes mellitus patient. Front Genet 14:1113314CrossRefPubMedPubMedCentral Li D, Li S, Zhou J, Zheng L, Liu G, Ding C, Yuan X (2023) Case Report: Identification of a rare nonsense mutation in the POC1A gene by NGS in a diabetes mellitus patient. Front Genet 14:1113314CrossRefPubMedPubMedCentral
17.
go back to reference Shohdy KS, Bareja R, Sigouros M, Wilkes DC, Dorsaint P, Manohar J, Bockelman D, Xiang JZ, Kim R, Ohara K et al (2021) Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors. NPJ Genom Med 6(1):66CrossRefPubMedPubMedCentral Shohdy KS, Bareja R, Sigouros M, Wilkes DC, Dorsaint P, Manohar J, Bockelman D, Xiang JZ, Kim R, Ohara K et al (2021) Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors. NPJ Genom Med 6(1):66CrossRefPubMedPubMedCentral
18.
go back to reference Paul MS, Michener SL, Pan H, Chan H, Pfliger JM, Rosenfeld JA, Lerma VC, Tran A, Longley MA, Lewis RA et al (2024) A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3. Am J Hum Genet 111(1):96–118CrossRefPubMed Paul MS, Michener SL, Pan H, Chan H, Pfliger JM, Rosenfeld JA, Lerma VC, Tran A, Longley MA, Lewis RA et al (2024) A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3. Am J Hum Genet 111(1):96–118CrossRefPubMed
19.
go back to reference Chung HL, Mao X, Wang H, Park YJ, Marcogliese PC, Rosenfeld JA, Burrage LC, Liu P, Murdock DR, Yamamoto S et al (2020) De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy. Am J Hum Genet 106(5):717–725CrossRefPubMedPubMedCentral Chung HL, Mao X, Wang H, Park YJ, Marcogliese PC, Rosenfeld JA, Burrage LC, Liu P, Murdock DR, Yamamoto S et al (2020) De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy. Am J Hum Genet 106(5):717–725CrossRefPubMedPubMedCentral
20.
go back to reference Li X, Zhang Q, Guo P, Fu J, Mei L, Lv D, Wang J, Lai D, Ye S, Yang H et al (2021) Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res 31(1):52–61CrossRefPubMed Li X, Zhang Q, Guo P, Fu J, Mei L, Lv D, Wang J, Lai D, Ye S, Yang H et al (2021) Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res 31(1):52–61CrossRefPubMed
22.
go back to reference Graziano B, Wang L, White OR, Kaplan DH, Fernandez-Abascal J, Bianchi L (2024) Glial KCNQ K+ channels control neuronal output by regulating GABA release from glia in C. elegans. Neuron Graziano B, Wang L, White OR, Kaplan DH, Fernandez-Abascal J, Bianchi L (2024) Glial KCNQ K+ channels control neuronal output by regulating GABA release from glia in C. elegans. Neuron
23.
go back to reference Nappi M, Barrese V, Carotenuto L, Lesca G, Labalme A, Ville D, Smol T, Rama M, Dieux-Coeslier A, Rivier-Ringenbach C et al (2022) Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy. Proc Natl Acad Sci USA 119(15):e2116887119CrossRefPubMedPubMedCentral Nappi M, Barrese V, Carotenuto L, Lesca G, Labalme A, Ville D, Smol T, Rama M, Dieux-Coeslier A, Rivier-Ringenbach C et al (2022) Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy. Proc Natl Acad Sci USA 119(15):e2116887119CrossRefPubMedPubMedCentral
24.
go back to reference Soh H, Springer K, Doci K, Balsbaugh JL, Tzingounis AV (2022) KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3. Proc Natl Acad Sci U S A 119(13):e2117640119CrossRefPubMedPubMedCentral Soh H, Springer K, Doci K, Balsbaugh JL, Tzingounis AV (2022) KCNQ2 and KCNQ5 form heteromeric channels independent of KCNQ3. Proc Natl Acad Sci U S A 119(13):e2117640119CrossRefPubMedPubMedCentral
25.
go back to reference Li T, Wu K, Yue Z, Wang Y, Zhang F, Shen H (2021) Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. Mol Cell 81(1):25-37.e24CrossRefPubMed Li T, Wu K, Yue Z, Wang Y, Zhang F, Shen H (2021) Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. Mol Cell 81(1):25-37.e24CrossRefPubMed
26.
go back to reference Varghese N, Moscoso B, Chavez A, Springer K, Ortiz E, Soh H, Santaniello S, Maheshwari A, Tzingounis AV (2023) KCNQ2/3 Gain-of-Function Variants and Cell Excitability: Differential Effects in CA1 versus L2/3 Pyramidal Neurons. J Neurosci 43(38):6479–6494CrossRefPubMedPubMedCentral Varghese N, Moscoso B, Chavez A, Springer K, Ortiz E, Soh H, Santaniello S, Maheshwari A, Tzingounis AV (2023) KCNQ2/3 Gain-of-Function Variants and Cell Excitability: Differential Effects in CA1 versus L2/3 Pyramidal Neurons. J Neurosci 43(38):6479–6494CrossRefPubMedPubMedCentral
27.
go back to reference Musella S, Carotenuto L, Iraci N, Baroli G, Ciaglia T, Nappi P, Basilicata MG, Salviati E, Barrese V, Vestuto V et al (2022) Beyond retigabine: Design, synthesis, and pharmacological characterization of a potent and chemically stable neuronal Kv7 channel activator with anticonvulsant activity. J Med Chem 65(16):11340–11364CrossRefPubMedPubMedCentral Musella S, Carotenuto L, Iraci N, Baroli G, Ciaglia T, Nappi P, Basilicata MG, Salviati E, Barrese V, Vestuto V et al (2022) Beyond retigabine: Design, synthesis, and pharmacological characterization of a potent and chemically stable neuronal Kv7 channel activator with anticonvulsant activity. J Med Chem 65(16):11340–11364CrossRefPubMedPubMedCentral
28.
go back to reference Edmond MA, Hinojo-Perez A, Wu X, Perez Rodriguez ME, Barro-Soria R (2022) Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels. Elife p 11 Edmond MA, Hinojo-Perez A, Wu X, Perez Rodriguez ME, Barro-Soria R (2022) Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels. Elife p 11
29.
go back to reference Zhang HB, Heckman L, Niday Z, Jo S, Fujita A, Shim J, Pandey R, Al Jandal H, Jayakar S, Barrett LB et al (2022) Cannabidiol activates neuronal Kv7 channels. Elife p 11 Zhang HB, Heckman L, Niday Z, Jo S, Fujita A, Shim J, Pandey R, Al Jandal H, Jayakar S, Barrett LB et al (2022) Cannabidiol activates neuronal Kv7 channels. Elife p 11
30.
go back to reference Vanoye CG, Desai RR, Ji Z, Adusumilli S, Jairam N, Ghabra N, Joshi N, Fitch E, Helbig KL, McKnight D et al (2022) High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity. JCI Insight 7(5) Vanoye CG, Desai RR, Ji Z, Adusumilli S, Jairam N, Ghabra N, Joshi N, Fitch E, Helbig KL, McKnight D et al (2022) High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity. JCI Insight 7(5)
31.
go back to reference Ottosson NE, SilveråEjneby M, Wu X, Estrada-Mondragón A, Nilsson M, Karlsson U, Schupp M, Rognant S, Jepps TA, Konradsson P et al (2021) Synthetic resin acid derivatives selectively open the hKV 7.2/7.3 channel and prevent epileptic seizures. Epilepsia 62(7):1744–1758CrossRefPubMed Ottosson NE, SilveråEjneby M, Wu X, Estrada-Mondragón A, Nilsson M, Karlsson U, Schupp M, Rognant S, Jepps TA, Konradsson P et al (2021) Synthetic resin acid derivatives selectively open the hKV 7.2/7.3 channel and prevent epileptic seizures. Epilepsia 62(7):1744–1758CrossRefPubMed
32.
go back to reference D’Adamo MC, Catacuzzeno L, Di Giovanni G, Franciolini F, Pessia M (2013) K(+) channelepsy: progress in the neurobiology of potassium channels and epilepsy. Front Cell Neurosci 7:134CrossRefPubMedPubMedCentral D’Adamo MC, Catacuzzeno L, Di Giovanni G, Franciolini F, Pessia M (2013) K(+) channelepsy: progress in the neurobiology of potassium channels and epilepsy. Front Cell Neurosci 7:134CrossRefPubMedPubMedCentral
33.
go back to reference Efthymiou S, Scala M, Nagaraj V, Ochenkowska K, Komdeur FL, Liang RA, Abdel-Hamid MS, Sultan T, Barøy T, Van Ghelue M et al (2024) Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain Efthymiou S, Scala M, Nagaraj V, Ochenkowska K, Komdeur FL, Liang RA, Abdel-Hamid MS, Sultan T, Barøy T, Van Ghelue M et al (2024) Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain
34.
go back to reference Goto A, Ishii A, Shibata M, Ihara Y, Cooper EC, Hirose S (2019) Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia 60(9):1870–1880CrossRefPubMed Goto A, Ishii A, Shibata M, Ihara Y, Cooper EC, Hirose S (2019) Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia 60(9):1870–1880CrossRefPubMed
35.
go back to reference Soldovieri MV, Freri E, Ambrosino P, Rivolta I, Mosca I, Binda A, Murano C, Ragona F, Canafoglia L, Vannicola C et al (2020) Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy. Pharmacol Res 160:105200CrossRefPubMed Soldovieri MV, Freri E, Ambrosino P, Rivolta I, Mosca I, Binda A, Murano C, Ragona F, Canafoglia L, Vannicola C et al (2020) Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy. Pharmacol Res 160:105200CrossRefPubMed
36.
go back to reference Kanyo R, Wang CK, Locskai LF, Li J, Allison WT, Kurata HT (2020) Functional and behavioral signatures of Kv7 activator drug subtypes. Epilepsia 61(8):1678–1690CrossRefPubMed Kanyo R, Wang CK, Locskai LF, Li J, Allison WT, Kurata HT (2020) Functional and behavioral signatures of Kv7 activator drug subtypes. Epilepsia 61(8):1678–1690CrossRefPubMed
37.
go back to reference Ostacolo C, Miceli F, Di Sarno V, Nappi P, Iraci N, Soldovieri MV, Ciaglia T, Ambrosino P, Vestuto V, Lauritano A et al (2020) Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuronal Kv7 Channel Activators. J Med Chem 63(1):163–185CrossRefPubMed Ostacolo C, Miceli F, Di Sarno V, Nappi P, Iraci N, Soldovieri MV, Ciaglia T, Ambrosino P, Vestuto V, Lauritano A et al (2020) Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuronal Kv7 Channel Activators. J Med Chem 63(1):163–185CrossRefPubMed
38.
go back to reference Miceli F, Millevert C, Soldovieri MV, Mosca I, Ambrosino P, Carotenuto L, Schrader D, Lee HK, Riviello J, Hong W et al (2022) KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism. EBioMedicine 81:104130CrossRefPubMedPubMedCentral Miceli F, Millevert C, Soldovieri MV, Mosca I, Ambrosino P, Carotenuto L, Schrader D, Lee HK, Riviello J, Hong W et al (2022) KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism. EBioMedicine 81:104130CrossRefPubMedPubMedCentral
39.
go back to reference Kim JE, Lee DS, Kim MJ, Kang TC (2019) PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination. Cell Death Dis 10(8):545CrossRefPubMedPubMedCentral Kim JE, Lee DS, Kim MJ, Kang TC (2019) PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination. Cell Death Dis 10(8):545CrossRefPubMedPubMedCentral
40.
go back to reference Soldovieri MV, Boutry-Kryza N, Milh M, Doummar D, Heron B, Bourel E, Ambrosino P, Miceli F, De Maria M, Dorison N et al (2014) Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum Mutat 35(3):356–367CrossRefPubMed Soldovieri MV, Boutry-Kryza N, Milh M, Doummar D, Heron B, Bourel E, Ambrosino P, Miceli F, De Maria M, Dorison N et al (2014) Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum Mutat 35(3):356–367CrossRefPubMed
41.
go back to reference Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B et al (2019) Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. Front Neurosci 13:1135CrossRefPubMedPubMedCentral Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B et al (2019) Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. Front Neurosci 13:1135CrossRefPubMedPubMedCentral
42.
go back to reference Nicholson AM, Finch NA, Thomas CS, Wojtas A, Rutherford NJ, Mielke MM, Roberts RO, Boeve BF, Knopman DS, Petersen RC et al (2014) Progranulin protein levels are differently regulated in plasma and CSF. Neurology 82(21):1871–1878CrossRefPubMedPubMedCentral Nicholson AM, Finch NA, Thomas CS, Wojtas A, Rutherford NJ, Mielke MM, Roberts RO, Boeve BF, Knopman DS, Petersen RC et al (2014) Progranulin protein levels are differently regulated in plasma and CSF. Neurology 82(21):1871–1878CrossRefPubMedPubMedCentral
43.
go back to reference Mortzfeld BM, Taubenheim J, Fraune S, Klimovich AV, Bosch TCG (2018) Stem Cell Transcription Factor FoxO Controls Microbiome Resilience in Hydra. Front Microbiol 9:629CrossRefPubMedPubMedCentral Mortzfeld BM, Taubenheim J, Fraune S, Klimovich AV, Bosch TCG (2018) Stem Cell Transcription Factor FoxO Controls Microbiome Resilience in Hydra. Front Microbiol 9:629CrossRefPubMedPubMedCentral
44.
go back to reference Begemann A, Acuña MA, Zweier M, Vincent M, Steindl K, Bachmann-Gagescu R, Hackenberg A, Abela L, Plecko B, Kroell-Seger J et al (2019) Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes. Mol Med 25(1):6CrossRefPubMedPubMedCentral Begemann A, Acuña MA, Zweier M, Vincent M, Steindl K, Bachmann-Gagescu R, Hackenberg A, Abela L, Plecko B, Kroell-Seger J et al (2019) Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes. Mol Med 25(1):6CrossRefPubMedPubMedCentral
45.
go back to reference Hengel H, Bosso-Lefèvre C, Grady G, Szenker-Ravi E, Li H, Pierce S, Lebigot É, Tan TT, Eio MY, Narayanan G et al (2020) Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun 11(1):595CrossRefPubMedPubMedCentral Hengel H, Bosso-Lefèvre C, Grady G, Szenker-Ravi E, Li H, Pierce S, Lebigot É, Tan TT, Eio MY, Narayanan G et al (2020) Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun 11(1):595CrossRefPubMedPubMedCentral
46.
go back to reference Chakrabarty S, Govindaraj P, Sankaran BP, Nagappa M, Kabekkodu SP, Jayaram P, Mallya S, Deepha S, Ponmalar JNJ, Arivinda HR et al (2021) Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. J Neurol 268(6):2192–2207CrossRefPubMedPubMedCentral Chakrabarty S, Govindaraj P, Sankaran BP, Nagappa M, Kabekkodu SP, Jayaram P, Mallya S, Deepha S, Ponmalar JNJ, Arivinda HR et al (2021) Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. J Neurol 268(6):2192–2207CrossRefPubMedPubMedCentral
Metadata
Title
Novel KCNQ2 missense variant expands the genotype spectrum of DEE7
Authors
Chao Wang
JinXia Zhai
YongJun Chen
Publication date
17-06-2024
Publisher
Springer International Publishing
Published in
Neurological Sciences
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI
https://doi.org/10.1007/s10072-024-07655-w