Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: TFG
SNOMEDCT: 715665006, 723826007;
Cytogenetic location: 3q12.2 Genomic coordinates (GRCh38): 3:100,709,290-100,748,967 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q12.2 | ?Spastic paraplegia 57, autosomal recessive | 615658 | Autosomal recessive | 3 |
| Hereditary motor and sensory neuropathy, Okinawa type | 604484 | Autosomal dominant | 3 |
The TFG gene encodes a protein that plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules (summary by Beetz et al., 2013).
Mencinger et al. (1997) identified the complete TFG gene by searching for ESTs that were similar to the N-terminal regions of EWS (133450) and FUS (137070). TFG encodes a predicted 400-amino acid protein with a putative N-terminal coiled-coil region. On Northern blots, the 2.2-kb TFG mRNA was expressed in all tissues tested. Greco et al. (1995) stated that a coiled-coil structure and ubiquitous expression are features shared by all NTRK1-activating genes as well as genes that activate other tyrosine kinase protooncogenes.
By PCR-based cloning of a cDNA library from a fetal brain, Ishiura et al. (2012) identified 4 TFG isoforms generated by alternative splicing. TFG was ubiquitously expressed, including in the spinal cord and dorsal root ganglia. Immunohistochemical studies showed fine granular immunostaining of TFG in the cytoplasm of motor neurons in the spinal cord of neurologically normal human controls.
Ishiura et al. (2012) demonstrated that the TFG gene contains 8 exons; they also identified a new exon, 7b, which is included in some of the transcripts.
Greco et al. (1995) localized the TFG gene to chromosome 3 by PCR of a hybrid panel. Mencinger et al. (1997) mapped the TFG gene to 3q11-q12 by fluorescence in situ hybridization.
TFG/NTRK1 Fusion Gene
Greco et al. (1995) stated that approximately 50% of papillary thyroid carcinomas (see 188550) are associated with rearrangements of the RET (164761) and NTRK1 (191315) transmembrane receptor tyrosine kinase protooncogenes. The rearrangements juxtapose the tyrosine kinase domain to 5-prime sequences from unrelated loci, yielding chimeric proteins with ectopic, constitutive tyrosine kinase activity. In one tumor, Greco et al. (1995) found a chimeric oncogene, which they designated TRKT3, in which 1,412 nucleotides of the NTRK1 gene were fused to 598 nucleotides from the TFG gene. Greco et al. (1995) determined that the TRKT3 oncogene encodes a predicted 592-amino acid chimeric protein that forms multimeric complexes in vivo.
TFG/NR4A3 Fusion Gene
Hisaoka et al. (2004) identified an NR4A3 (600542)/TFG fusion gene in an extraskeletal myxoid chondrosarcoma (EMC; 612237) derived from a Japanese patient. The fusion occurred between exon 6 of the TFG gene and exon 3 of the NR4A3 gene. Hisaoka et al. (2004) used the symbol NOR1 for the NR4A3 gene.
In the mouse, Beetz et al. (2013) found expression of the Tfg gene in the central nervous system and in the eye. Tfg was highly abundant in Purkinje cells, which are essential for motor function, and in deep cortical layers, including layer V, which contains motoneurons of the motor cortex. Imaging of cortical neurons showed that Tfg was present in punctate structures and colocalized with markers of ER exit sites in axons and dendrites. In growth cones, Tfg associated with ER tubules that underwent extensions and retractions over time. Knockdown of TFG in COS-7 cells using siRNA resulted in alteration of the highly branched organization of the tubular ER network. Peripheral ER tubules collapsed onto the microtubule skeleton, and mitochondria were abnormally clustered around the microtubule organizing center. The findings suggested that interfering with normal TFG function disrupts organization of the tubular ER network.
Hereditary Motor and Sensory Neuropathy, Okinawa Type
In affected members of 4 Japanese families with Okinawa hereditary motor and sensory neuropathy (HMSNO; 604484), Ishiura et al. (2012) identified a heterozygous mutation in the TFG gene (P285L; 602498.0001). Two of the families were from the Kansai region (Maeda et al., 2007) and 2 were from Okinawa. The mutation was found by exome capture of the candidate region identified by linkage analysis. Expression of the mutant TFG protein resulted in mislocalization and TDP43 (TARDBP; 605078)-inclusion-body formation in cultured cells. These findings suggested a pathogenic link to amyotrophic lateral sclerosis (ALS; 105400), in which TDP43 inclusions are found, and suggested that alteration of vesicle trafficking or RNA-mediated mechanisms might be involved in motor neuron degeneration in HMSNO.
Lee et al. (2013) identified a heterozygous P285L mutation in the TFG gene in affected members of a Korean family with HMSNO. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases. TFG levels in patient peripheral nerves were similar to those in controls. The phenotype was characterized by young adult onset of proximal muscle weakness, with cramping and fasciculations, and distal sensory impairment. Some of the patients had hand tremor early in the disease course, and MRI showed fatty infiltration in proximal muscles of the lower limbs.
In affected members of a large Taiwanese family with adult-onset motor and sensory axonal neuropathy, Tsai et al. (2014) identified a heterozygous missense mutation in the TFG gene (G269V; 602498.0003). The G269V mutant protein formed intracellular insoluble aggregates and colocalized with wildtype TFG, thus depleting soluble functional wildtype TFG. The large cytoplasmic G269V aggregates did not stain with TDP43 (605078). Knockdown of TFG using siRNA significantly reduced protein secretion from the ER and reduced cell viability, which could be rescued by wildtype TFG, but not by G269V TFG. The findings suggested that defects in the protein secretory pathways can cause dysfunction of the peripheral nervous system.
Autosomal Recessive Spastic Paraplegia 57
In 2 sibs of Indian descent with autosomal recessive spastic paraplegia-57 (SPG57; 615658), Beetz et al. (2013) identified a homozygous missense mutation in the TFG gene (R106C; 602498.0002). The mutation was found by linkage analysis and whole-exome sequencing. In vitro functional expression assays showed that the mutant protein was expressed but that it interfered with the ability of TFG to assemble into an octameric complex, which is critical for normal function. The patients had early-onset severe spastic paraplegia resulting in an inability to walk, as well as optic atrophy and peripheral neuropathy. The findings implicated a role for TFG in long-term axonal maintenance via its role in ER microtubular architecture and function.
In affected members of 4 Japanese families with Okinawa hereditary motor and sensory neuropathy (HMSNO; 604484), Ishiura et al. (2012) identified a heterozygous 854C-T transition in the TFG gene, resulting in a pro285-to-leu (P285L) substitution at a highly conserved residue in the P/Q-rich domain in the C-terminal region. The mutation was not observed in 964 Japanese control chromosomes or in several exome databases. Two of the families were from the Kansai region and 2 were from Okinawa, and haplotype analysis suggested 2 independent origins of the mutation. The disorder was characterized clinically by young adult onset of proximal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. Neuropathologic examination of 1 patient showed TFG-immunopositive inclusion bodies in the motor neurons of the facial, hypoglossal, and abducens nuclei, and the spinal cord, as well as in the sensory neurons of the dorsal root ganglia. Inclusions were not found in glial cells. The TFG-immunopositive inclusions colocalized with ubiquitin deposition. In addition, phosphorylated TDP43 (605078)-positive inclusions were identified in motor and sensory neurons in the spinal cord; some inclusions were positive for both TFG and TDP43. There was also fragmentation of the Golgi apparatus in HMSNO motor neurons. Expression of the mutant TFG protein resulted in mislocalization and TDP43-inclusion-body formation in cultured cells. These findings suggested a pathogenic link to amyotrophic lateral sclerosis (ALS; 105400), in which TDP43 inclusions are found, and suggested that alteration of vesicle trafficking or RNA-mediated mechanisms might be involved in motor neuron degeneration in HMSNO.
Lee et al. (2013) identified a heterozygous P285L mutation in the TFG gene in affected members of a Korean family with HMSNO. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases. TFG levels in patient peripheral nerves were similar to those in controls. The phenotype was characterized by young adult onset of proximal muscle weakness with cramping and fasciculations, and distal sensory impairment. Some of the patients had hand tremor early in the disease course, and MRI showed fatty replacement in proximal muscles of the lower limbs.
In 2 sibs of Indian descent with autosomal recessive spastic paraplegia-57 (SPG57; 615658), Beetz et al. (2013) identified a homozygous c.316C-T transition in the TFG gene, resulting in an arg106-to-cys (R106C) substitution at a highly conserved residue in the coiled-coil domain, which is important for TFG oligomerization. The mutation, which was found by linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server or 1000 Genomes Project databases, or in 100 local control individuals. In vitro functional expression assays showed that the mutant protein was expressed but that the mutation interfered with the ability of TFG to assemble into an octamer complex, which is critical for normal function.
In 16 affected members of a large multigenerational Taiwanese family with Okinawa hereditary motor and sensory neuropathy (HMSNO; 604484), Tsai et al. (2014) identified a heterozygous c.806G-T transversion in the TFG gene, resulting in a gly269-to-val (G269V) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, in 24 in-house control exomes, or in 1,140 ethnically matched control chromosomes. Expression of the mutation in HEK293 cells showed reduced amounts of the mutant protein compared to wildtype, but mRNA levels were similar to wildtype. The G269V mutant protein formed intracellular insoluble aggregates and colocalized with wildtype TFG, thus depleting soluble functional wildtype TFG. The large cytoplasmic G269V aggregates did not stain with TDP43 (605078). Knockdown of TFG using siRNA significantly reduced protein secretion from the ER and reduced cell viability, which could be rescued by wildtype TFG, but not by G269V TFG.
Beetz, C., Johnson, A., Schuh, A. L., Thakur, S., Varga, R.-E., Fothergill, T., Hertel, N., Bomba-Warczak, E., Thiele, H., Nurnberg, G., Altmuller, J., Saxena, R., Chapman, E. R., Dent, E. W., Nurnberg, P., Audhya, A. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc. Nat. Acad. Sci. 110: 5091-5096, 2013. [PubMed: 23479643] [Full Text: https://doi.org/10.1073/pnas.1217197110]
Greco, A., Mariani, C., Miranda, C., Lupas, A., Pagliardini, S., Pomati, M., Pierotti, M. A. The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Molec. Cell Biol. 15: 6118-6127, 1995. [PubMed: 7565764] [Full Text: https://doi.org/10.1128/MCB.15.11.6118]
Hisaoka, M., Ishida, T., Imamura, T., Hashimoto, H. TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer 40: 325-328, 2004. [PubMed: 15188455] [Full Text: https://doi.org/10.1002/gcc.20044]
Ishiura, H., Sako, W., Yoshida, M., Kawarai, T., Tanabe, O., Goto, J., Takahashi, Y., Date, H., Mitsui, J., Ahsan, B., Ichikawa, Y., Iwata, A., and 16 others. The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. Am. J. Hum. Genet. 91: 320-329, 2012. [PubMed: 22883144] [Full Text: https://doi.org/10.1016/j.ajhg.2012.07.014]
Lee, S.-S., Lee, H. J., Park, J.-M., Hong, Y. B., Park, K.-D., Yoo, J. H., Koo, H., Jung, S.-C., Park, H. S., Lee, J. H., Lee, M. G., Hyun, Y. S., Nakhro, K., Chung, K. W., Choi, B.-O. Proximal dominant hereditary motor and sensory neuropathy with proximal dominance association with mutation in the TRK-fused gene. JAMA Neurol. 70: 607-615, 2013. [PubMed: 23553329] [Full Text: https://doi.org/10.1001/jamaneurol.2013.1250]
Maeda, K., Kaji, R., Yasuno, K., Jambaldorj, J., Nodera, H., Takashima, H., Nakagawa, M., Makino, S., Tamiya, G. Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity. J. Hum. Genet. 52: 907-914, 2007. [PubMed: 17906970] [Full Text: https://doi.org/10.1007/s10038-007-0193-7]
Mencinger, M., Panagopoulos, I., Andreasson, P., Lassen, C., Mitelman, F., Aman, P. Characterization and chromosomal mapping of the human TFG gene involved in thyroid carcinoma. Genomics 41: 327-331, 1997. [PubMed: 9169129] [Full Text: https://doi.org/10.1006/geno.1997.4625]
Tsai, P.-C., Huang, Y.-H., Guo, Y.-C., Wu, H.-T., Lin, K.-P., Tsai, Y.-S., Liao, Y.-C., Liu, Y.-T., Liu, T.-T., Kao, L.-S., Yet, S.-F., Fann, M.-J., Soong, B.-W., Lee, Y.-C. A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function. Neurology 83: 903-912, 2014. [PubMed: 25098539] [Full Text: https://doi.org/10.1212/WNL.0000000000000758]