Expanding the Phenotype Associated With the<i>NEFL</i>Mutation

Objectives To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). Methods Combined analysis of new patients with NEFL-related CMT, identified from those attending clinics at the participating institutions, and all previously reported cases from the literature. Results Five new unrelated patients with CMT carrying heterozygous NEFL mutations (N98S, P8R and L311P) were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 55% and 75% of kindreds, respectively. De novo mutations were identified in eight patients. Loss of large-myelinated fibres was a uniform feature in 21 sural nerve biopsies, and ‘onion bulb’ formations and/or thin myelin sheaths were observed in 67%. The neurophysiological phenotype was broad but most patients carrying the mutations E90K and N98S had all reported upper limb motor conduction velocities <38 m/s. Age of symptoms onset was ≤ 3 years in 25 cases. Pyramidal tract signs were described in 13 patients and seven patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia or cerebellar atrophy on brain MRI. Conclusions NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

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“…an overlapping myopathic-neurogenic phenotype 39 and also in association with CMT 40 but no clinical details were available for the latter.…”

Section: Neuromuscularmentioning

confidence: 99%

Genetic and clinical characteristics ofNEFL-related Charcot-Marie-Tooth disease

Horga

Laurá

Jaunmuktane

et al. 2017

J Neurol Neurosurg Psychiatry

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“…In contrast, myopathies primarily affect muscle structure and/or function with clinically affected muscles either proximal, such as in limb girdle muscle dystrophy, and/or distal in distal myopathies. Although the distinction between primary muscle and primary neuronal neuromuscular diseases might a priori seem obvious, there are significant clinical and genetic overlaps between these diseases [2][3][4]. In this review, we describe how mutations in functionally related RNA-binding proteins (RBPs) are associated with both muscle and motor neuron diseases, and how these mutations participate in compromising the neuromuscular system.…”

Section: Introductionmentioning

confidence: 99%

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

Picchiarelli¹,

Dupuis²

2020

CST

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A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.

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“…14 Mutations in the NEFL gene have been associated with motor neuron diseases in mice and Charcot-Marie-Tooth disease in human. 15 The mutation of NEFL could cause a painful predominantly sensory neuropathy. 16 Signal transducer and activator of transcription (STAT3) has been proved to be involved in cell differentiation of the nervous system.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway

et al. 2019

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Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

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Expanding the Phenotype Associated With theNEFLMutation

Cited by 35 publications

References 28 publications

Genetic and clinical characteristics ofNEFL-related Charcot-Marie-Tooth disease

Genetic and clinical characteristics ofNEFL-related Charcot-Marie-Tooth disease

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligation via the neurofilament light polypeptide-dependent signal transducer and activator of transcription signaling pathway

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