Alternative titles; symbols
HGNC Approved Gene Symbol: NEFL
SNOMEDCT: 717012004, 719980006;
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38): 8:24,950,955-24,956,612 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.2 | Charcot-Marie-Tooth disease, dominant intermediate G | 617882 | Autosomal dominant | 3 |
| Charcot-Marie-Tooth disease, type 1F | 607734 | Autosomal dominant; Autosomal recessive | 3 | |
| Charcot-Marie-Tooth disease, type 2E | 607684 | Autosomal dominant | 3 |
The NEFL gene encodes the neurofilament light polypeptide, a subunit that forms type IV intermediate filament heteropolymers, which are a major component of the neuronal cytoskeleton (summary by Agrawal et al., 2014).
Cytoplasmic intermediate filaments (IF) can be divided into 5 subclasses based on their biochemical properties, immunologic specificity and tissue distribution: keratin (139350, 148030) filaments in epithelial cells, vimentin (193060) filaments in cells of mesenchymal origin, desmin (125660) in muscle cells, glial filaments in astrocytes, and neurofilaments in neurons. The different types of intermediate filament proteins share common structural features. Neurofilaments are composed of 3 neuron-specific proteins with apparent molecular masses of 68 kD (NFL), 125 kD (NFM), and 200 kD (NFH) on SDS-gel electrophoresis (summary by Julien et al., 1987).
Julien et al. (1987) isolated the genomic copy of the human NFL gene using an NFL cDNA probe. After transfection into mouse L-cells, the cloned gene was transcribed into 2 mRNAs approximately 2.6 and 4.3 kb long. The different sequence data show that the intermediate filament proteins contain a similar alpha-helical domain of conserved length capable of forming coiled-coils.
The vimentin, desmin, and glial fibrillary acidic protein genes each contains 8 introns at identical positions, 6 of the introns being located within the regions encoding alpha-helical sequences. A majority of the introns in the less closely related keratin genes occurred at similar or identical positions. The NFL gene was found by Julien et al. (1987) to have an unexpected intron-exon organization in that it entirely lacks introns at positions found in other members of the intermediate filament gene family. It contains only 3 introns. Possible evolutionary explanations were discussed. Lees et al. (1988) analyzed the structure of the NFH subunit. They concluded that divergence of the neural IF lineage from the nonneural IF lineage probably involved ancestral IF gene duplication rather than RNA-mediated transposition.
By Southern blot analysis of DNA from hybrid cell panels and by in situ hybridization, Hurst et al. (1987) assigned the NEFL gene to 8p21. Somerville et al. (1988) also assigned this gene, which they symbolized NF68, to 8p21 by in situ hybridization. In addition, they found secondary hybridization sites at the centromeric region of chromosome 2 and on the long arm of chromosome 7, which are putative loci for other intermediate filaments. The corresponding gene for NFL, as well as that for middle-molecular-mass neurofilament protein, appears to be on chromosome 14 in the mouse (Levy et al., 1987).
Previtali et al. (2003) detected MTMR2 (603557) in all cytoplasmic compartments of myelin-forming Schwann cells, as well as in the cytoplasm of non-myelin-forming Schwann cells and both sensory and motor neurons. In contrast, MTMR2 was detected in the nucleus of Schwann cells and motor neurons, but not in the nucleus of sensory neurons. NFL interacted with MTMR2 in yeast 2-hybrid screenings using both fetal brain and peripheral nerve libraries and was found to interact with MTMR2 in both Schwann cells and neurons.
Charcot-Marie-Tooth Disease 2E
In a large Russian family with an axonal form of Charcot-Marie-Tooth disease (CMT2E; 607684), Mersiyanova et al. (2000) identified a gln333-to-pro mutation in the NEFL gene (Q333P; 162280.0001).
Using a transient expression system, Brownlees et al. (2002) demonstrated that the pro8-to-arg (P8R; 162280.0003) and Q333P (162280.0001) mutant NEFL proteins, which cause CMT2E, disrupted both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurons. CMT mutant neurofilaments also perturbed the localization of mitochondria in neurons. Accumulations of neurofilaments are a pathologic feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS; 105400), Alzheimer disease (104300), Parkinson disease (168600), dementia with Lewy bodies (127750), and diabetic neuropathy (see 603933). The authors concluded that their results demonstrated that aberrant neurofilament assembly and transport can induce neurologic disease and further implicated defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.
Charcot-Marie-Tooth Disease Type 1F
Jordanova et al. (2003) identified 6 missense mutations and a 3-bp deletion (162280.0004) in the NEFL gene in patients with autosomal dominant demyelinating CMT1F (607734). Three of these mutations occurred in codon 8 (see, e.g., 162280.0003). Yamamoto et al. (2004) presented evidence suggesting that the 3-bp deletion in the NEFL gene is a polymorphic variant rather than a disease-causing mutation in Japan.
Charcot-Marie-Tooth Disease, Dominant Intermediate G
In 4 affected members of a 3-generation German family with dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG; 617882). Zuchner et al. (2004) identified a heterozygous missense mutation in the NEFL gene (E396K; 162280.0010). The mutation, which was found by direct sequencing of the NEFL gene, segregated with the disorder in the family. Two asymptomatic family members also carried the mutation: they were 21 years of age, possibly suggesting age-related incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.
Elbracht et al. (2014) identified heterozygosity for the E396K mutation in the NEFL gene in 8 members of a multigenerational family with onset of CMTDIG since infancy or early childhood as well as in an unrelated patient (patient 9) with CMTDIG who had onset at age 50; he had no family history of CMT. The discrepancy in the phenotype among patients with the same mutation suggested additional genetic modifiers and broadened the phenotypic spectrum associated with this mutation. Functional studies of the variant were not performed.
Berciano et al. (2015) identified heterozygosity for the E396K mutation in the NEFL gene in 4 affected members of a Spanish family with CMTDIG. The variant, which was found by exome sequencing of candidate disease genes, was confirmed by Sanger sequencing and segregated with the disorder. Functional studies of the variant and studies of patient cells were not performed.
In a Spanish woman and her son with CMTDIG, Berciano et al. (2016) identified a heterozygous missense mutation in the NEFL gene (N98S; 162280.0011). The mutation was found by exome sequencing. Functional studies of the variant were not performed.
NEFL Aggregation Studies
Lin et al. (2005) reported that p190RhoGEF (612790), an RNA-binding protein that binds to a destabilizing element in NEFL mRNA, is involved in aggregation of NEFL protein and is implicated in the pathogenesis of motor neuron degeneration. The 190RhoGEF protein coaggregated with unassembled NEFL protein, and that coaggregation was associated with downregulation of parent NEFL mRNA in neuronal cells. Coexpression of medium neurofilament (NFM; 162250) increased NF assembly and reduced RNA-triggered aggregation as well as loss of solubility of NEFL protein. siRNA-induced downregulation of p190RhoGEF not only reduced aggregation and promoted assembly of NEFL and NFM, but also caused reversal of aggregation and recovery of NF assembly in transfected cells. Examination of transgenic models of motor neuron disease showed that prominent aggregates of p190RhoGEF and NEFL and downregulation of NEFL expression occurred in degenerating motor neurons of mice expressing untranslated NEFL RNA or a G93A-mutant SOD1 (147450) transgene. Moreover, aggregates of p190RhoGEF and NEFL appeared as early pathologic changes in presymptomatic G93A-mutant SOD1 transgenic mice. Lin et al. (2005) concluded that p190RhoGEF is involved in aggregation of NEFL protein and proposed that aggregation of p190RhoGEF and NEFL may be an upstream event triggering neurotoxicity in motor neuron disease.
Rebelo et al. (2016) identified NEFL as a gene with the potential to cause abnormal and toxic protein aggregations as a result of a stop-loss mutation, i.e., a mutation that extends the 3-prime translation frame beyond the normal stop codon, resulting in the addition of cryptic amyloidogenic elements (CAE). Cultured neuronal cells expressing such frameshift NEFL mutations showed prominent toxic protein aggregations in the cytoplasm as well as rounded cells and a lack of axon-like projections, indicating that they would be pathogenic and thus could likely result in neurologic disorders. Similar findings were observed for frameshift mutations in the NEFH gene (162230).
Perez-Olle et al. (2004) analyzed the effects of 5 NFL mutations on the assembly and intracellular distribution of intermediate filaments (IFs), and compared the results with those obtained previously for other NFL mutations. Although all NFL mutants affected the formation of IF networks, there were differential effects on the assembly of IFs depending on the mutation. Defective transport of the mutant NFL subunits was observed for all the CMT-linked NFL mutations, but the characteristics of this defect also depended on the specific mutation. The authors concluded that defects in the assembly and transport of NFs are common to all NFL mutants studied to that time, but the exact nature of the defect appeared to be correlated with each mutant genotype.
In a review of published studies of patients with NEFL mutations, Miltenberger-Miltenyi et al. (2007) concluded that there are no obvious genotype/phenotype correlations. However, the authors noted that mutations in the head domain of NEFL may cause more severe slowing of nerve conduction velocities than mutations in the coil 2B domain.
Using homologous recombination in embryonic stem cells, Zhu et al. (1997) generated mice bearing a targeted disruption of the NFL gene. The absence of NFL protein resulted in dramatic reduction in the levels of Nfm and Nfh proteins in the brain and sciatic nerve, while increases for other cytoskeletal proteins, such as tubulin and GAP43 (162060), were detected. Despite a lack of neurofilaments and hypotrophy of axons, the NFL knockout mice developed normally and did not exhibit any overt phenotypes. However, in both heterozygous and homozygous NFL mutant mice, Zhu et al. (1997) observed a reduction in the normal regeneration of myelinated axons following crush injury of peripheral nerves. Using electron microscopy of nerve segments distal to the crush site, Zhu et al. (1997) detected abundant clusters of axonal sprouts that were indicative of retarded maturation of regenerating fibers in NFL null mice. Long-term analysis indicated that neurofilament-deficient axons have the capacity to regrow and to remyelinate, albeit at a slower rate. Zhu et al. (1997) concluded that neurofilaments play a role in the maturation of regenerating myelinated axons.
Hirokawa and Takeda (1998) reviewed contributions gene targeting studies had made to understanding the role of each of the neurofilament component proteins in neurofilament formation and in determination of the axonal caliber.
Using immunohistochemistry and immunoblots experiments, Nguyen et al. (2001) detected a hyperphosphorylation of neurofilament proteins associated with abnormally elevated p25/p35 (see 603460) ratio and Cdk5 (123831) activity in the spinal cord of transgenic mice with a gly37-to-arg (G37R) mutation in the SOD1 gene (147450.0001), a mouse model of amyotrophic lateral sclerosis (ALS; 105400). Nguyen et al. (2001) bred the Sod1 mutant transgene onto neurofilament mutant backgrounds and observed that the absence of NFL provoked an accumulation of unassembled neurofilament subunits in the perikaryon of motor neurons. Using double immunofluorescence microscopy, Nguyen et al. (2001) confirmed that Cdk5 and p25 colocalize with perikaryal neurofilament accumulations in SOD1(G37R) mice on the neurofilament mutant background. Immunoblotting showed that the occurrence of perikaryal neurofilament accumulations in SOD1(G37R) mice was associated with a reduction in the phosphorylation of microtubule-associated protein tau (157140), another p25/Cdk5 substrate. The absence of the NFL subunit extended the average life span of SOD1(G37R) mice. Nguyen et al. (2001) hypothesized that perikaryal accumulations of neurofilament proteins in motor neurons may alleviate ALS pathogenesis in Sod1 mutant mice by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates.
Adebola et al. (2015) found that knockin mice heterozygous or homozygous for the Nefl P8R (162280.0003) mutation were behaviorally similar to wildtype animals. The authors attributed the lack of phenotype to possible background modifier genes. In contrast, knockin mice heterozygous for the Nefl N98S (162280.0011) mutation developed tremor and a hindlimb clasping phenotype as early as 1 month of age. Abnormal neuronal processes in the cerebral cortex and pons were present as soon as 7 days after birth, and these animals had multiple inclusions in cell bodies and proximal axons of spinal cord neurons.
In a large Mordovian (Russian) family with autosomal dominant Charcot-Marie-Tooth disease of the axonal form (CMT2E; 607684), Mersiyanova et al. (2000) found linkage to chromosome 8p21 and identified a 998A-C transversion in the first exon of the NEFL gene, resulting in a gln333-to-pro (Q333P) mutation in a conserved region. This alteration was not found in 180 normal chromosomes. No mutations in this gene were found in 20 unrelated CMT2 patients or in 26 others with an undetermined form of CMT. The authors suggested the designation CMT2E for this disorder.
In cultured mouse motor neurons, Zhai et al. (2007) found that expression of Q333P- and P8R (162280.0003)-mutant NEFL led to progressive degeneration and loss of neuronal viability. Degenerating motor neurons showed fragmentation and loss of neuritic processes associated with disruption of the neurofilament network and aggregation of the NEFL protein. Coexpression of mutant NEFL with wildtype HSPB1 (602195) diminished aggregation of mutant NEFL, induced reversal of mutant NEFL aggregates, and reduced mutant NEFL-induced loss of motor neuron viability. Similarly, expression of mutant HSPB1 (S135F; 602195.0001), which causes CMT2F (606595) also led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL protein. The 2 proteins were found to associate together, and the S135F-mutant HSPB1 had a dominant effect. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E and CMT2F.
Georgiou et al. (2002) described a large 5-generation Slovenian family with autosomal dominant Charcot-Marie-Tooth disease type 2E (CMT2E; 607684) in which all 10 affected members had a 64C-T transition in exon 1 of the NEFL gene resulting in a pro22-to-ser (P22S) substitution. Disease onset in most patients was in the first decade of life. The presenting symptoms were difficulty in walking or running, due to a slowly progressive distal weakness and wasting of the lower limbs. A steppage gait, pes cavus, and hammertoes were typically present. Over a period of 20 years after disease onset, two-thirds of patients developed upper limb involvement resulting in claw hands. All patients were ambulatory 20 to 30 years after onset.
Fabrizi et al. (2004) identified the P22S mutation in affected members of an Italian family with CMT2E. Sural nerve biopsy showed loss of large myelinated axons and a few swollen axons encased in a thin myelin sheath. Neurofilaments were grouped in a random orientation.
Sasaki et al. (2006) noted that the P22S mutation abolishes a phosphorylation sequence in the head domain of NEFL. In vitro functional expression studies in isolated human cells and in rat cortical neuron cultures showed that the mutant P22S or P22T NEFL proteins formed large aggregates and assembled into short twisty threads thinner than 10 nm filaments. Those threads associated with each other at their ends and entangled into large aggregates. The structure disturbance occurred during oligomer formation. Further studies showed that the pro22 mutations abolished phosphorylation of residue thr21 by CDK5 (123831), which normally suppresses filament assembly. However, the mutant proteins were able to be phosphorylated by protein kinase A to the same extent as wildtype, which inhibited aggregate formation in cortical neurons. The results indicated that the pro22 CMT mutation induces abnormal filament aggregates by disrupting proper oligomer formation, but demonstrated that the formation of these aggregates could be mitigated by phosphorylation.
In members of a Belgian family with Charcot-Marie-Tooth disease type 2E (CMT2E; 607684), De Jonghe et al. (2001) demonstrated a double transition at nucleotides 22 to 23 (CC to AG) in exon 1 of the NEFL gene, resulting in a pro8-to-arg (P8R) substitution. The patients presented with a classic but rather severe CMT phenotype with onset in the second decade. Nerve conduction velocities were sometimes severely slowed.
Jordanova et al. (2003) found the P8R mutation in affected members of a family segregating CMT1F (607734), In another family with CMT1F and in a sporadic patient with a similar phenotype, they found mutations in the same codon.
Perez-Olle et al. (2004) demonstrated that the P8R mutation as well as 2 other mutations at this codon resulted in accumulation of the mutant NFL protein in the cell body and the proximal segments of neuronal processes.
In affected members of an Austrian family with CMT2E, Miltenberger-Miltenyi et al. (2007) identified a heterozygous 23C-G transversion in the NEFL gene, resulting in a P8R substitution in the head domain of the protein. Disease onset was before age 15 years in all but 1 patient. The disorder was slowly progressive but resulted in a severe and disabling phenotype. Another unrelated patient with sporadic disease also had a P8R mutation.
In cultured mouse motor neurons, Zhai et al. (2007) found that expression of Q333P (162280.0001)- and P8R-mutant NEFL led to progressive degeneration and loss of neuronal viability. Degenerating motor neurons showed fragmentation and loss of neuritic processes associated with disruption of the neurofilament network and aggregation of the NEFL protein. Coexpression of mutant NEFL with wildtype HSPB1 (602195) diminished aggregation of mutant NEFL, induced reversal of mutant NEFL aggregates, and reduced mutant NEFL-induced loss of motor neuron viability. Similarly, expression of mutant HSPB1 (S135F; 602195.0001), which causes CMT2F (606595) also led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL protein. The 2 proteins were found to associate together, and the S135F-mutant HSPB1 had a dominant effect. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E and CMT2F.
In a Bulgarian family in which 4 members over 3 generations had Charcot-Marie-Tooth disease type 1F (CMT1F; 607734), Jordanova et al. (2003) identified a heterozygous 3-bp deletion (1581delGAG) in exon 4 of the NEFL gene.
Yamamoto et al. (2004) presented evidence suggesting that the 3-bp deletion in the NEFL gene, which results in deletion of a glutamine at codon 528, is a polymorphic variant rather than a disease-causing mutation in Japan.
In a 71-year-old man with Charcot-Marie-Tooth disease type 2E (CMT2E; 607684), Leung et al. (2006) identified a heterozygous 13-bp duplication/insertion at nucleotide 61 in exon 1 of the NEFL gene, predicted to result in termination at codon 21. Transient transfection experiments showed that the mutated NEFL could not form filaments by itself, and in the presence of mutated NEFL, wildtype NEFL formed only short filaments and alpha-internexin (605338) filaments collapsed into aggregates.
In 4 affected members of a large Austrian family with Charcot-Marie-Tooth disease type 2E (CMT2E; 607684), Miltenberger-Miltenyi et al. (2007) identified a heterozygous 281T-C transition in the NEFL gene, resulting in a leu94-to-pro (L94P) substitution in a highly conserved residue in the coil 1a domain. Disease onset was in the second decade of life with pes cavus, progressive plantar extensor weakness, and distal lower limb atrophy and weakness. Two patients became wheelchair-bound. Electrophysiologic studies showed intermediate motor nerve conduction velocities consistent with axonal pathology.
In a Japanese man, born of consanguineous parents, with demyelinating Charcot-Marie-Tooth disease type 1F (CMT1F; 607734), Abe et al. (2009) identified a homozygous 418G-T transversion in the NEFL gene, resulting in a glu140-to-ter (E140X) substitution. He had onset of gait problems before age 10 years, upper and lower limb muscle atrophy and weakness, distal sensory loss, waddling gait, and severely decreased motor nerve conduction velocity (13.8 m/s). A similarly affected brother needed a wheelchair by age 40, but neither parent was affected. Abe et al. (2009) postulated that the nonsense mutation would result in loss of function, in contrast to missense mutations which result in toxic gain of function, and concluded that homozygous nonsense mutations in the NEFL gene cause a recessive disorder.
In 4 Palestinian sibs with a severe, progressive peripheral neuropathy beginning in early childhood (CMT1F; 607734), Yum et al. (2009) identified a homozygous 628G-T transversion in the NEFL gene, resulting in a glu210-to-ter (E210X) substitution. The unaffected consanguineous parents were heterozygous for the mutation. Visual evoked responses were prolonged in 3 of 4 children, suggesting the involvement of central nervous system axons. Sural nerve biopsy of 1 patient showed lack of immunostaining for NEFL, decreased numbers of myelinated axons, and some regenerating axons. Intermediate filaments were not present in remaining myelinated axons. In vitro functional expression studies showed that the mutant NEFL did not accumulate properly, suggesting an inability to form filaments or enhanced degradation, consistent with a loss of function. Although Yum et al. (2009) referred to this phenotype as an 'axonal' neuropathy, the median nerve conduction velocities in all affected patients ranged from 14 to 25 m/s, which is more consistent with a 'demyelinating' neuropathy, as in CMT1F.
In a mother and her 3 sons with a variant of axonal Charcot-Marie-Tooth disease type 2E (CMT2E; 607684) presenting as congenital myopathy, Agrawal et al. (2014) identified a heterozygous c.1261C-T transition in the NEFL gene, resulting in an arg421-to-ter (R421X) substitution. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 139), 1000 Genomes Project, or Exome Sequencing Project databases. Analysis of patient cells showed that the mutation did not result in nonsense-mediated mRNA decay. Western blot analysis and immunofluorescent studies of patient muscle samples showed that the NEFL protein was present and localized properly to motor endplates at nerve terminals. Faint bands of full-length NEFL were found in muscle from 2 affected members and 2 controls; the presence of a truncated protein related to the R421X mutation could not be evaluated because of the low overall abundance of NEFL in skeletal muscle and a nonspecific or cross-reacting band at the molecular weight. Agrawal et al. (2014) hypothesized that the translated truncated protein, which may be stable, could interfere with wildtype NEFL in mature neurofilament heteropolymers. The patients presented in infancy with hypotonia, delayed motor development, and distal muscle weakness; all became wheelchair-dependent at different ages.
In 4 affected members of a 3-generation German family with dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG; 617882), Zuchner et al. (2004) identified a heterozygous c.1189G-A transition in exon 3 of the NEFL gene, resulting in a glu397-to-lys (E397K) substitution at a conserved residue at the end of the rod domain. (Fabrizi et al. (2007) noted that the numbering of this mutation was changed to a c.1186G-A transition, resulting in a glu396-to-lys (E396K) substitution, based on an updated reference sequence.) The mutation, which was found by direct sequencing of the NEFL gene, segregated with the disorder in the family and was not found in 65 normal controls. Two asymptomatic family members also carried the mutation: they were 21 years of age, possibly suggesting age-related incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.
Fabrizi et al. (2007) identified heterozygosity for the E396K mutation in the NEFL gene in 2 Italian sibs (family E) with CMTDIG.
Elbracht et al. (2014) identified heterozygosity for the E396K mutation in the NEFL gene in 8 members of a multigenerational family with onset of CMTDIG since infancy or early childhood as well as in an unrelated patient (patient 9) with CMTDIG who had onset at age 50; he had no family history of CMT. The discrepancy in the phenotype among patients with the same mutation suggested additional genetic modifiers and broadened the phenotypic spectrum associated with this mutation.
In 4 members of a Spanish family with CMTDIG, Berciano et al. (2015) identified heterozygosity for the E396K mutation in the NEFL gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Variant Server databases, as well as 90 in-house genomes.
In a mother and son with dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG; 617882), Berciano et al. (2016) identified a heterozygous c.293A-G transition in the NEFL gene, resulting in an asn98-to-ser (N98S) substitution at a conserved residue. The mutation was found by whole-exome sequencing after excluding mutations in several spinocerebellar ataxia and CMT genes. Functional studies of the variant were not performed.
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