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, Vol. 83, 104234, 09.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -