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.
CONCLUSIONS: 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.
BACKGROUND: DFG, BMBF, Hartwell Foundation, National Institute for Neurological Disorders and Stroke, IDDRC, ENGIN, NIH, ITMAT, ILAE, RES and GRIN.
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.
CONCLUSIONS: 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.
BACKGROUND: DFG, BMBF, Hartwell Foundation, National Institute for Neurological Disorders and Stroke, IDDRC, ENGIN, NIH, ITMAT, ILAE, RES and GRIN.
摘要：
目的：成纤维细胞生长因子12（FGF12）可能是神经元网络活动的重要调节剂，并与发育性和癫痫性脑病（DEE）有关。我们试图确定FGF12相关疾病的潜在病理机制。
方法：通过已发表的病例报告确定了FGF12致病变异的患者，GeneMatcher和自己的病例集的整个外显子组测序。通过在神经元样细胞（ND7/23）中共表达野生型和突变型FGF12与钠通道NaV1.2或NaV1.6，包括其β-1和β-2钠通道亚基（SCN1B和SCN2B），研究了两种错义和两种拷贝数变体（CNV）的功能后果。
结果：确定了FGF12中的四种变体用于功能分析：自闭症谱系障碍患者中的一种新型FGF12变体和先前发表的受DEE影响的患者中的三种变体。我们证明了野生型和突变型FGF12对NaV1.2和NaV1.6通道的差异调节作用。这里,FGF12变体导致对NaV1.2和NaV1.6的复杂动力学影响,包括快速和缓慢失活中的功能损失以及获得变化。
结论：我们可以证明FGF12对NaV1.2和NaV1.6的详细调节作用，并证实了FGF12对神经元网络活性的复杂作用。我们的发现扩展了与FGF12变异相关的表型谱，并阐明了潜在的病理机制。FGF12相关疾病中的特定变体可能适合于用钠通道阻断剂进行精确治疗。
背景：DFG，BMBF,Hartwell基金会,国家神经疾病和中风研究所，IDDRC,ENGIN,NIH,ITMAT,ILAE,RES和GRIN。
方法：通过已发表的病例报告确定了FGF12致病变异的患者，GeneMatcher和自己的病例集的整个外显子组测序。通过在神经元样细胞（ND7/23）中共表达野生型和突变型FGF12与钠通道NaV1.2或NaV1.6，包括其β-1和β-2钠通道亚基（SCN1B和SCN2B），研究了两种错义和两种拷贝数变体（CNV）的功能后果。
结果：确定了FGF12中的四种变体用于功能分析：自闭症谱系障碍患者中的一种新型FGF12变体和先前发表的受DEE影响的患者中的三种变体。我们证明了野生型和突变型FGF12对NaV1.2和NaV1.6通道的差异调节作用。这里,FGF12变体导致对NaV1.2和NaV1.6的复杂动力学影响,包括快速和缓慢失活中的功能损失以及获得变化。
结论：我们可以证明FGF12对NaV1.2和NaV1.6的详细调节作用，并证实了FGF12对神经元网络活性的复杂作用。我们的发现扩展了与FGF12变异相关的表型谱，并阐明了潜在的病理机制。FGF12相关疾病中的特定变体可能适合于用钠通道阻断剂进行精确治疗。
背景：DFG，BMBF,Hartwell基金会,国家神经疾病和中风研究所，IDDRC,ENGIN,NIH,ITMAT,ILAE,RES和GRIN。
