A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot–Marie–Tooth disease

Jun, Fu; Yuan, Yun

doi:10.1016/j.nmd.2017.09.018

Cited by 17 publications

(21 citation statements)

References 23 publications

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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

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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

“…There are 34 reported CMT2E/1F NFL mutations in human patients ( Figure 1) (Doppler et al, 2017;Fu & Yuan, 2018;Horga et al, 2017;Lerat et al, 2019;Sainio et al, 2018). These are primarily missense mutations, but there are also frameshift, deletion, and nonsense F I G U R E 1 Schematic of the known CMT2E/1F NFL mutations.…”

Section: Choice Of Mutantsmentioning

confidence: 99%

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

2019

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“… (A) Sequencing traces of the c.1099C>T variant in the family members show that both parents of the patients are heterozygous carriers of the mutation. (B) NEFL protein domains are depicted, and the localization of the reported missense and nonsense variants is indicated (modified from references 17 and 25 ). The nonsense variant A367* identified in this study is shown in red.…”

Section: Resultsmentioning

confidence: 99%

“… 13 , 16 , 17 Homozygous p.Glu140* mutation was described in 1 patient with gait disturbance and progressive muscle weakness since school age, 16 p.Glu210* in 4 siblings with slowly progressive distal muscle weakness and atrophy starting at approximately 1.5 years, 13 and p.Glu163* in an adolescent girl with muscle weakness and gait disturbances during the first decade. 17 Although neurofilament aggregation is well documented for dominant NEFL mutations, 12 , 13 , 26 as well as in other neurodegenerative disorders, 2 , 3 the molecular consequences of recessive nonsense mutations in NEFL have not been fully investigated. Neuronal specificity of NEFL has previously prevented studying the nonsense mutations in detail, and especially in cells with endogenous levels of mutant NEFL mRNA.…”

Section: Discussionmentioning

confidence: 99%

“… 14 , 15 All reported recessive NEFL mutations have been homozygous nonsense variants. 13 , 16 , 17 Elucidation of the disease mechanism of the recessive variants in humans has been complicated by the restricted neuronal expression of NEFL. 18 Thus, it is not known if the homozygous nonsense variants cause disease through aggregation effects mediated by a truncated protein or by the loss of NEFL protein through nonsense-mediated messenger RNA (mRNA) decay (NMD).…”

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Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy

Sainio¹,

Ylikallio

Mäenpää

et al. 2018

Neurol Genet

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ObjectiveWe used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot-Marie-Tooth (CMT) disease.MethodsMotor neurons were differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons.ResultsWe show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient's cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neurofilaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most downregulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA.ConclusionsThe strict neuronal specificity of neurofilament has hindered the mechanistic studies of recessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. We propose that the neurofilament accumulation, a common feature of many neurodegenerative diseases, mimics the absence of NEFL seen in recessive CMT if aggregation prevents the proper localization of wild-type NEFL in neurons. Our results suggest that the removal of NEFL as a proposed treatment option is harmful in humans.

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A review and analysis of the clinical literature on Charcot–Marie–Tooth disease caused by mutations in neurofilament protein L

2021

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Charcot–Marie–Tooth disease (CMT) is one of the most common inherited neurological disorders and can be caused by mutations in over 100 different genes. One of the causative genes is NEFL on chromosome 8 which encodes neurofilament light protein (NEFL), one of five proteins that co‐assemble to form neurofilaments. At least 34 different CMT‐causing mutations in NEFL have been reported which span the head, rod, and tail domains of the protein. The majority of these mutations are inherited dominantly, but some are inherited recessively. The resulting disease is classified variably in clinical reports based on electrodiagnostic studies as either axonal (type 2; CMT2E), demyelinating (type 1; CMT1F), or a form intermediate between the two (dominant intermediate; DI‐CMTG). In this article, we first present a brief introduction to CMT and neurofilaments. We then collate and analyze the data from the clinical literature on the disease classification, age of onset and electrodiagnostic test results for the various mutations. We find that mutations in the head, rod, and tail domains can all cause disease with early onset and profound neurological impairment, with a trend toward greater severity for head domain mutations. We also find that the disease classification does not correlate with specific mutation or domain. In fact, different individuals with the same mutation can be classified as having axonal, demyelinating, or dominant intermediate forms of the disease. This suggests that the classification of the disease as CMT2E, CMT1F or DI‐CMTG has more to do with variable disease presentation than to differences in the underlying disease mechanism, which is most likely primarily axonal in all cases.

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A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot–Marie–Tooth disease

Cited by 17 publications

References 23 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

Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy

A review and analysis of the clinical literature on Charcot–Marie–Tooth disease caused by mutations in neurofilament protein L

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