Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease

Abstract

Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

“…However the frequency is higher than the level of 31.2% in Japanese CMT1 patients (Ikegami et al, 1997). Mersiyanova et al, 2000bHuehne et al, 2003Bort et al, 1997Silander et al, 1998Jordanova et al, 2003Mostacciuolo et al, 2001 Patients with the CMT1A duplication were excluded. b Patients neither CMT1A duplication nor causative mutation in PMP22, MPZ and GJB1.…”

“…NEFL gene encoding the neurofilament light chain plays an important role in axonal structure that includes an extensive fibrous network in the cytoplasm of the neuron. Recently, mutations in NEFL gene have been found in patients with CMT2E (Mersiyanova et al, 2000a) and early onset severe CMT phenotypes (Jordanova et al, 2003).…”

Axon Transport and Neuropathy

“…162280) lead to complex disease phenotypes that can have either AR or AD inheritance and have normal nerve conduction velocity by electrophysiologic studies (CMT2E) or reduced nerve conduction velocity (CMT1F). 74,75 …”

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

“…Three mutations (Pro22Ser, Leu268Pro and del322Cys-326Asn) have been reported to be associated with giant axonal neuropathies and secondary demyelination (Fabrizi et al 2004(Fabrizi et al , 2007, whereas the other mutations (Glu89Lys and Glu397Lys) were found to be associated with onion bulb formations and loss of large myelinated fibers, but not giant axonal neuropathy (Jordanova et al 2003;Züchner et al 2004).…”

“…Mutations in the NEFL gene were originally reported to be associated with CMT2E (De Jonghe et al 2001;Fabrizi et al 2004). However, because some patients had markedly reduced NCVs, it was suggested that NEFL neuropathy was also relevant with CMT1F (Jordanova et al 2003).…”