Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14

Miura, Satoshi; Kosaka, Kengo; Fujioka, Ryuta; Uchiyama, Y.; Shimojo, Tomofumi; Morikawa, Takuya; Irie, Azusa; Taniwaki, Takayuki; Shibata, Hiroki

doi:10.1016/j.ejmg.2018.07.005

Cited by 19 publications

(16 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 Loss-of-function variants in FHF4 (FGF14) have also been associated with cerebellar dysfunction (and occasionally cerebellar atrophy) as the cause of spinocerebellar ataxia type 27 (MIM: 609307). 50,51 In contrast, structural and functional abnormalities of the cerebellum were not observed in FHF2-DEE. Different gene expression patterns may explain this difference as FHF1 and FHF4 are both highly expressed in the cerebellum while FHF2 is not.…”

mentioning

confidence: 87%

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fry

Marra

Derrick

et al. 2021

The American Journal of Human Genetics

View full text Add to dashboard Cite

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v ) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi-and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v 1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function.Voltage-activated sodium channels (Na v ) play an essential role in the generation and spread of action potentials in excitable tissues. 1,2 Variants in Na v channels and their regulatory partners are a major cause of infantile-onset developmental and epileptic encephalopathies (DEEs). 3,4 DEEs are typically associated with developmental delay or regression, treatment-resistant seizures, and electroencephalographic abnormalities. 5,6 The developmental consequences of DEEs are due to frequent epileptiform activity in combination with the direct effects of the genetic variant. 7,8 Fibroblast growth factor homologous factors (FHFs) are intracellular proteins that bind to the C-terminal domain of Na v channels to modulate their function and location. [9][10][11][12] FHFs were initially identified due to their homology with fibroblast growth factors (FGFs). 13 However, FHFs are not secreted by cells and have only limited ability to activate FGF receptors. 9,14,15 There are four FHF genes in mammals (often referred to by their FGF names): FHF1 (FGF12 [MIM: 601513]), FHF2 (FGF13 [MIM: 300070]), FHF3 (FGF11 [MIM: 601514]), and FHF4 (FGF14 [MIM: 601515]). 9 The FHF genes have multiple transcription initiation sites. The alternative first exons produces multiple isoforms with variable N-terminal domains. 16 The isoforms differ in their localization and ability to regulate Na v channels. 9 FHF2, located at Xq26.3-q27.1, is highly expressed in the developing and adult brain. 9,13 FHF2 is also expressed in endocrine tissues, ovaries, skeletal muscle, and the myocardium of the developing heart. [17][18][19] FHF2 has been implicated...

show abstract

mentioning

confidence: 87%

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fry

Marra

Derrick

et al. 2021

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…One year later, heterozygous mutations in FGF14 were identified as causative of an autosomal dominant form of spinocerebellar ataxia, successively classified as SCA type 27 [309]. Less than 50 cases are currently described in the literature [310][311][312]. A recent review of published cases [310] concludes that early-onset tremor (mean age of 12.1 ± 10.5 years) is the typical manifestation at the onset of disease and it is followed by gait ataxia later in life (mean age of 23.7 ± 16.7 years) accompanied by limb ataxia, dysarthria, or nystagmus.…”

Section: Metabolic Disorders With Eamentioning

confidence: 99%

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Garone

Capuano

Travaglini

et al. 2020

IJMS

View full text Add to dashboard Cite

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

show abstract

“…Linkage analysis assigned the disease locus to chromosome region 13q34, and a candidate gene approach revealed a mutation c.434 T > C/p.F145S in the fibroblast growth factor 14 ( FGF14 ) gene [ 80 ]. The findings of additional FGF14 mutations (e.g., a 1 bp deletion c.487delA/p.D163fsX12 [ 81 ] and a missense mutation (c.529A > T/p.K177X) [ 82 ]) in autosomal dominant ataxias confirm that FGF14 is the disease gene in SCA27.…”

Section: Sca27mentioning

confidence: 99%

Spinocerebellar ataxias (SCAs) caused by common mutations

Müller¹

2021

Neurogenetics

View full text Add to dashboard Cite

The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

show abstract

Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14

Cited by 19 publications

References 17 publications

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

Spinocerebellar ataxias (SCAs) caused by common mutations

Contact Info

Product

Resources

About