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Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series

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Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. / Seiffert, Simone; Pendziwiat, Manuela; Bierhals, Tatjana; Goel, Himanshu; Schwarz, Niklas; van der Ven, Amelie; Boßelmann, Christian Malte; Lemke, Johannes; Syrbe, Steffen; Willemsen, Marjolein Hanna; Hedrich, Ulrike Barbara Stefanie; Helbig, Ingo; Weber, Yvonne.

in: EBIOMEDICINE, Jahrgang 83, 104234, 09.2022.

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

Harvard

Seiffert, S, Pendziwiat, M, Bierhals, T, Goel, H, Schwarz, N, van der Ven, A, Boßelmann, CM, Lemke, J, Syrbe, S, Willemsen, MH, Hedrich, UBS, Helbig, I & Weber, Y 2022, 'Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series', EBIOMEDICINE, Jg. 83, 104234. https://doi.org/10.1016/j.ebiom.2022.104234

APA

Seiffert, S., Pendziwiat, M., Bierhals, T., Goel, H., Schwarz, N., van der Ven, A., Boßelmann, C. M., Lemke, J., Syrbe, S., Willemsen, M. H., Hedrich, U. B. S., Helbig, I., & Weber, Y. (2022). Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. EBIOMEDICINE, 83, [104234]. https://doi.org/10.1016/j.ebiom.2022.104234

Vancouver

Seiffert S, Pendziwiat M, Bierhals T, Goel H, Schwarz N, van der Ven A et al. Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. EBIOMEDICINE. 2022 Sep;83. 104234. https://doi.org/10.1016/j.ebiom.2022.104234

Bibtex

@article{e75a29e425af467c8ce8e06a3cac61c0,
title = "Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series",
abstract = "OBJECTIVE: Fibroblast Growth Factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders.METHODS: Patients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense and two copy number variants (CNVs) were studied by co-expression of wildtype and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B).RESULTS: Four variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by DEE. We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on NaV1.2 and NaV1.6, including loss- as well as gain-of function changes in fast and slow inactivation.INTERPRETATION: We could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.FUNDING: DFG, BMBF, Hartwell Foundation, National Institute for Neurological Disorders and Stroke, IDDRC, ENGIN, NIH, ITMAT, ILAE, RES and GRIN.",
keywords = "Autism Spectrum Disorder/genetics, Brain Diseases, Fibroblast Growth Factors/genetics, Humans, NAV1.2 Voltage-Gated Sodium Channel/metabolism, NAV1.6 Voltage-Gated Sodium Channel/metabolism, Sodium Channel Blockers, Sodium Channels",
author = "Simone Seiffert and Manuela Pendziwiat and Tatjana Bierhals and Himanshu Goel and Niklas Schwarz and {van der Ven}, Amelie and Bo{\ss}elmann, {Christian Malte} and Johannes Lemke and Steffen Syrbe and Willemsen, {Marjolein Hanna} and Hedrich, {Ulrike Barbara Stefanie} and Ingo Helbig and Yvonne Weber",
note = "Copyright {\textcopyright} 2022 The Author(s). Published by Elsevier B.V. All rights reserved.",
year = "2022",
month = sep,
doi = "10.1016/j.ebiom.2022.104234",
language = "English",
volume = "83",
journal = "EBIOMEDICINE",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series

AU - Seiffert, Simone

AU - Pendziwiat, Manuela

AU - Bierhals, Tatjana

AU - Goel, Himanshu

AU - Schwarz, Niklas

AU - van der Ven, Amelie

AU - Boßelmann, Christian Malte

AU - Lemke, Johannes

AU - Syrbe, Steffen

AU - Willemsen, Marjolein Hanna

AU - Hedrich, Ulrike Barbara Stefanie

AU - Helbig, Ingo

AU - Weber, Yvonne

N1 - Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2022/9

Y1 - 2022/9

N2 - OBJECTIVE: Fibroblast Growth Factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders.METHODS: Patients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense and two copy number variants (CNVs) were studied by co-expression of wildtype and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B).RESULTS: Four variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by DEE. We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on NaV1.2 and NaV1.6, including loss- as well as gain-of function changes in fast and slow inactivation.INTERPRETATION: We could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.FUNDING: DFG, BMBF, Hartwell Foundation, National Institute for Neurological Disorders and Stroke, IDDRC, ENGIN, NIH, ITMAT, ILAE, RES and GRIN.

AB - OBJECTIVE: Fibroblast Growth Factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders.METHODS: Patients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense and two copy number variants (CNVs) were studied by co-expression of wildtype and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B).RESULTS: Four variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by DEE. We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on NaV1.2 and NaV1.6, including loss- as well as gain-of function changes in fast and slow inactivation.INTERPRETATION: We could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.FUNDING: DFG, BMBF, Hartwell Foundation, National Institute for Neurological Disorders and Stroke, IDDRC, ENGIN, NIH, ITMAT, ILAE, RES and GRIN.

KW - Autism Spectrum Disorder/genetics

KW - Brain Diseases

KW - Fibroblast Growth Factors/genetics

KW - Humans

KW - NAV1.2 Voltage-Gated Sodium Channel/metabolism

KW - NAV1.6 Voltage-Gated Sodium Channel/metabolism

KW - Sodium Channel Blockers

KW - Sodium Channels

U2 - 10.1016/j.ebiom.2022.104234

DO - 10.1016/j.ebiom.2022.104234

M3 - SCORING: Journal article

C2 - 36029553

VL - 83

JO - EBIOMEDICINE

JF - EBIOMEDICINE

SN - 2352-3964

M1 - 104234

ER -