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
Simone Seiffert,
Manuela Pendziwiat,
Tatjana Bierhals,
Himanshu Goel,
Niklas Schwarz,
Amelie van der Ven,
Christian Malte Boßelmann,
Johannes Lemke,
Steffen Syrbe,
Marjolein Hanna Willemsen,
Ulrike Barbara Stefanie Hedrich,
Ingo Helbig,
Yvonne Weber
Affiliations
Simone Seiffert
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Manuela Pendziwiat
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Tatjana Bierhals
Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Himanshu Goel
Hunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle, Callaghan, NSW, 2308, Australia
Niklas Schwarz
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Amelie van der Ven
Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Christian Malte Boßelmann
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Johannes Lemke
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
Steffen Syrbe
Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Marjolein Hanna Willemsen
Department of Clinical Genetics, Maastricht University Medical Centre Maastricht, The Netherlands; Department of Human Genetics, Radboud University Medical Centre Nijmegen, The Netherlands & Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
Ulrike Barbara Stefanie Hedrich
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Ingo Helbig
Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, USA; Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, USA
Yvonne Weber
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Department of Epileptology and Neurology, University of Aachen, Aachen, Germany; Corresponding author at: Department of Epileptology and Neurology, University of Aachen, Germany.
Summary: 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
