| Autor: |
Simone Seiffert, Manuela Pendziwiat, Tatjana Bierhals, Himanshu Goel, Niklas Schwarz, Amelie van der Ven, Christian Malte Boßelmann, Marjolein H. Willemsen, Ulrike B.S. Hedrich, Ingo Helbig, Yvonne G. Weber |
| Rok vydání: |
2021 |
| DOI: |
10.1101/2021.12.03.471090 |
| Popis: |
ObjectiveFibroblast 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.MethodsPatients 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 variants and two copy number variants (CNVs) were studied by co-expression of wild-type and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their functional active beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B).ResultsFour 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 developmental and epileptic encephalopathy (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 Nav 1.6, including loss- as well as gain-of function changes in fast inactivation as well as loss-of function changes in slow inactivation.InterpretationFor the first time, 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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