N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy

Yang, Yi; Gu, Liqiang; Burnette, W. Bryan; Li, Jun

doi:10.1016/j.jns.2016.04.007

Cited by 18 publications

(18 citation statements)

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“…Source . Data from Abe et al (), Agrawal et al (), Baets et al (), Benedetti et al (), Berciano et al (, ), Bhagavati et al (), Butinar et al (), Choi et al (, ), De Jonghe et al (), DiVincenzo et al (), Doppler et al (), Drew et al (), Elbracht et al (), Fabrizi et al (), Fabrizi et al (), Fu and Yuan (), Georgiou et al (), Hashiguchi et al (), Horga et al (), Jordanova et al (), Lerat et al (), Leung et al (), Lin et al (), Luigetti et al (), Manganelli et al (), Mersiyanova et al (), Miltenberger‐Miltenyi et al (), Noto et al (), Pisciotta et al (), Sainio et al (), Shin et al (), Sivera et al (), Werheid et al (), Yang et al (), Yoshihara et al (), Yum et al (), Züchner et al () [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Resultsunclassified

“…Genetically, the disease can be caused by mutations in >80 different genes (Timmerman, Strickland, & Züchner, 2014). Mutations in the low molecular weight neurofilament triplet protein (NFL) give rise to CMT disease that is classified as Type 2E or 1F depending on the clinical presentation (Horga et al, 2017;Yang, Gu, Burnette, & Li, 2016). One explanation for this variable diagnosis is that there is a loss of axon caliber which decreases conduction velocity without demyelination (Lancaster et al, 2018), thereby making what is an axonal (Type 2) disease sometimes appear to be demyelinating (Type 1).…”

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Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

2019

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Charcot–Marie–Tooth disease Type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament subunit proteins that co‐assemble to form neurofilaments in vivo. Prior studies on cultured cells have shown that CMT2E/1F mutations disrupt neurofilament assembly and lead to protein aggregation, suggesting a possible disease mechanism. However, electron microscopy of axons in peripheral nerve biopsies from patients has revealed accumulations of neurofilament polymers of normal appearance and no evidence of protein aggregates. To reconcile these observations, we reexamined the assembly of seven CMT2E/1F NFL mutants in cultured cells. None of the mutants assembled into homopolymers in SW13vim‐ cells, but P8R, P22S, L268/269P, and P440/441L mutant NFL assembled into heteropolymers in the presence of neurofilament protein M (NFM) alone, and N98S, Q332/333P, and E396/397K mutant NFL assembled in the presence of NFM and peripherin. P8R, P22S, N98S, L268/269P, E396/397K, and P440/441L mutant NFL co‐assembled into neurofilaments with endogenous NFL, NFM, and α‐internexin in cultured neurons, although the N98S and E396/397K mutants showed reduced filament incorporation, and the Q332/333P mutant showed limited incorporation. We conclude that all the mutants are capable of assembling into neurofilaments, but for some of the mutants this was dependent on the identity of the other neurofilament proteins available for co‐assembly, and most likely also their relative expression level. Thus, caution should be exercised when drawing conclusions about the assembly capacity of CMT2E/1F mutants based on transient transfections in cultured cells.

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Section: Resultsunclassified

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Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

2019

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“…NEFL plays a role in the nerve conduction velocity and axonal transport by encoding a neuronal protein that is vital for neurofilament formation. 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.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-7a ameliorates neuropathic pain in a rat model of spinal nerve ligationviathe 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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“…These aggregates appear to prevent the transport of NEFL to axons. Depletion of neurofilaments in axons would result in small axon calibre and thus a slower conduction velocity . This is in accordance with the study of the functional protein just described.…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature

Lerat

Magdelaine

Beauvais‐Dzugan

et al. 2019

J Peripheral Nervous Sys

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Neurofilaments are neuron‐specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot‐Marie‐Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype‐phenotype correlations have yet been established. Here, we report an additional case: a 69‐year‐old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next‐generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly). Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein.

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N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy

Cited by 18 publications

References 8 publications

Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

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

A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature

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