NEFH was first reported to be associated with autosomal dominant Charcot-Marie-Tooth disease type 2 in 2016 (Rebelo et al., PMID:27040688). This gene has also been implicated as a risk factor in ALS. NEFH encodes for the neurofilament heavy chain, a key component of neurofilaments, essential for the formation of cytoskeleton in neurons. Clinical features of patients with NEFH mutations include sensorimotor axonal neuropathy mainly characterized by distal lower limbs motor deficit with early and prominent involvement of proximal hip muscles. Additional common features include muscle cramps and increased creatine kinase level. All reported cases have frameshift mutations that cluster at the c-terminus end of the protein. Mutations result in loss of the stop codon and translation of the 3’-UTR. NEFH mutants carry a sequence extension of 45 extra amino acids, containing an amyloidogenic motif referred as cryptic amyloidogenic element of the 3’-UTR (CAE). This type of variant has been reported in 4 additional publications (PMIDs: 28709447, 28544463, 29587262, 30992180). NEFH physically interacts with NEFL, also a known CMT gene, forming neurofilament structures. The NEFH knockout mouse model showed diminished calibers of large myelinated axons in both central and peripheral nervous systems (Eder et at, PMID: 976343). Expression of frameshift mutants in cultured cells resulted in accumulation of prominent perinuclear aggregates, disrupted neurofilaments structures and cell toxicity (PMID:27040688). Expression of NEFH mutants in zebrafish resulted in abnormal motor neurons with truncated axons. A zebrafish rescue experiment showed that the WT human NEFH mRNA can rescue the morpholino injected fish, however, NEFH frameshift mutants were not able to rescue the phenotype (PMID:28544463). Expression of CMT-NEFH mutations in chick embryos resulted in neurofilament aggregates in the soma of neurons leading to neuronal cell death. Aggregates stain positive for activated caspase 3 and the autophagy marker p62 (Jacquier et al., PMID: 28709447). In summary, NEFH genetic and functional evidence was classified as DEFINITIVE.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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