Alternative titles; symbols
HGNC Approved Gene Symbol: LITAF
SNOMEDCT: 4183003;
Cytogenetic location: 16p13.13 Genomic coordinates (GRCh38) : 16:11,547,722-11,640,317 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.13 | Charcot-Marie-Tooth disease, type 1C | 601098 | Autosomal dominant | 3 |
The LITAF gene encodes a transcription factor, first identified as a regulator of TNF-alpha (TNF; 191160) gene expression (Takashiba et al., 1995). The LITAF gene product is an early endosomal membrane protein enriched in the peripheral nerves and Schwann cells (summary by Lee et al., 2011).
Lipopolysaccharide (LPS) is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor-alpha and other inflammatory mediators. Given the deleterious effects to the host of TNF-alpha, it is likely that TNF gene expression is tightly regulated. In studies pertaining to macrophage response to LPS, Takashiba et al. (1995) identified a novel DNA-binding domain that contains transcriptional activity located from -550 to -487 in the human TNF promoter. Sequence analysis of this fragment revealed the absence of any known binding sites for nuclear factor kappa-B (see 164011). Myokai et al. (1999) used this DNA fragment to isolate and purify a 60-kD protein binding to the fragment. They obtained its N-terminal sequence, which was used to design degenerate probes to screen a THP-1 cell cDNA library. A novel 1.8-kb cDNA clone was isolated and fully sequenced. Characterization of this cDNA clone revealed that its induction was dependent on LPS activation of the THP-1 cells; hence the name LPS-induced TNF-alpha factor (LITAF). Myokai et al. (1999) stated that the open reading frame of LITAF encodes a 228-amino acid protein. Inhibition of LITAF mRNA expression in THP-1 cells resulted in a reduction of TNF-alpha transcripts. Northern blot analysis detected a high level of LITAF mRNA expression predominantly in the placenta, peripheral blood leukocytes, lymph nodes, and spleen.
Street et al. (2003) stated that SIMPLE/LITAF is a widely expressed gene encoding a 161-amino acid protein.
By immunohistochemistry, Bennett et al. (2004) detected LITAF in the cytoplasm of sciatic nerve Schwann cells, as well as in adipocytes, mast cells, endothelial cells, and vascular smooth muscle cells.
Although 2 transcripts encoding different proteins (SIMPLE and LITAF) had been reported from the same gene, Saifi et al. (2005) could not confirm the existence of LITAF as originally identified by Myokai et al. (1999) and showed that the longer LITAF transcript appears to have resulted from a DNA sequencing error.
Lee et al. (2011) determined that the LITAF protein has a transmembrane domain embedded within the cysteine-rich region that anchors the protein to the membrane, suggesting that it is inserted into the membrane posttranslationally. In the mouse, Litaf was highly expressed in Schwann cells in peripheral nerves, with lower expression in brain and muscle. It showed a punctate pattern in the cytoplasm of primary Schwann cells. Endogenous Litaf localized to early endosomes, but not to late endosomes or lysosomes.
In adult mouse and rat sciatic nerve, Lee et al. (2013) found that Litaf localized in myelinating Schwann cells, but was not a structural component of the myelin sheath or axon. Litaf was enriched in the cytoplasmic regions at Schmidt-Lanterman incisures and paranodal domains. There was colocalization with the early endosome marker Rab5 (179512).
Studies of Polyak et al. (1997) in a human colorectal cell line indicated that LITAF expression was increased 10-fold in the presence of the tumor suppressor p53, which is known to regulate pathways leading to cellular growth arrest or apoptosis.
Street et al. (2003) suggested that LITAF may play a role in protein degradation pathways.
The LITAF gene contains 4 exons (Bennett et al., 2004).
By FISH, Myokai et al. (1999) mapped the LITAF gene to 16p13.3-p12.
Street et al. (2003) investigated the LITAF gene as the cause of Charcot-Marie-Tooth type 1C (CMT1C; 601098), which Street et al. (2002) had mapped in 2 affected pedigrees to a 9-cM interval on 16p that included the LITAF gene. They identified 3 missense mutations in the gene encoding a 161-amino acid protein, each in a separate CMT1C pedigree. The mutations were found to cluster and occurred at conserved residues, defining a domain of the LITAF protein having a critical role in peripheral nerve function. Western blot analysis suggested that 2 of the mutations, T115N (603795.0002) and W116G (603795.0003), do not alter the level of LITAF protein in peripheral blood lymphocytes. The LITAF transcript was found to be expressed in rat sciatic nerve, but its level of expression was not altered during development or in response to nerve injury. Street et al. (2003) noted that this finding was in sharp contrast to that seen for other known genes that cause CMT1.
Although 2 transcripts encoding different proteins (SIMPLE and LITAF) had been reported from the same gene, Saifi et al. (2005) could not confirm the existence of LITAF and showed that the LITAF transcript appears to have resulted from a DNA sequencing error.
Saifi et al. (2005) screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families, they identified 9 different nucleotide variations in SIMPLE (see 603795.0001, 603795.0004) that were not detected in control chromosomes. Saifi et al. (2005) concluded that SIMPLE mutations can occur de novo, associated with sporadic CMT1, and may convey both demyelinating and axonal forms.
Lee et al. (2011) found that CMT1C-associated LITAF mutations clustered within or around the transmembrane domain and caused mislocalization of the protein from the early endosomal membrane to the cytosol. Mutant proteins were less stable and more prone to aggregation compared to the wildtype protein. Aggregated proteins were degraded by both the proteasome and aggresome-autophagy pathways.
Tang et al. (2006) generated mice lacking Litaf in macrophages. They found that cytokine induction in Litaf-deficient macrophages was reduced compared with wildtype macrophages, and that mice lacking Litaf in macrophages were more resistant to LPS-induced lethality. By studying mouse macrophages lacking various Toll-like receptors (TLRs), Tang et al. (2006) found that expression of Litaf could be induced by LPS engagement of either Tlr2 (603028) or Tlr4 (603030), both of which required Myd88 (602170). In response to LPS, the Myd88-dependent Litaf pathway was independent of the Nfkb (see 164011) pathway, and p38-alpha (MAPK14; 600289) was required for Litaf phosphorylation and translocation to the nucleus.
Lee et al. (2013) found that transgenic mice carrying a homozygous Litaf mutation (W116G; 603795.0003) developed progressive motor and sensory impairment associated with decreased motor and sensory nerve conduction velocities similar to that observed in CMT1C. Peripheral nerves of mutant mice showed dysmyelination with reduced axon caliber and focal myelin infoldings near the paranodal and internodal regions. Myelin infolding was often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. The W116G mutant protein was partially mislocalized to the cytosol from the membrane. The findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. Myelin infolding and paranodal damage appeared to represent pathogenic precursors preceding demyelination and axonal degeneration in this disorder.
In a family (K1551) segregating CMT1C (601098), Street et al. (2003) identified a 334G-A transition in exon 3 of the LITAF gene, resulting in a gly112-to-ser (G112S) substitution. The family had previously been reported by Chance et al. (1990, 1992).
In affected members of a family with CMT1C and a patient with sporadic CMT1C, Saifi et al. (2005) identified the G112S mutation.
In a 2-year-old boy with severe demyelinating CMT, Meggouh et al. (2005) identified compound heterozygosity for 2 mutations: the G112S mutation in LITAF and a PMP22 duplication (601097.0001), which is the most common cause of CMT1A (118220). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. Meggouh et al. (2005) concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband.
In a family (K1550) segregating CMT1C (601098), Street et al. (2003) identified a 344C-A transversion in the LITAF gene, resulting in a thr115-to-asn (T115N) substitution. The family had previously been reported by Chance et al. (1990, 1992).
In a family segregating CMT1C (601098), Street et al. (2003) identified a 346T-G transversion in the LITAF gene, resulting in a trp116-to-gly (W116G) substitution.
In a sporadic case of CMT1C (601098), Saifi et al. (2005) identified a de novo heterozygous 364C-G transversion in exon 3 of the SIMPLE gene, resulting in a leu122-to-val (L122V) substitution.
In a German mother and son with CMT1C (601098), Gerding et al. (2009) identified a heterozygous 430G-A transition in exon 4 of the LITAF gene, resulting in a val144-to-met (V144M) substitution. The mutation was not observed in 400 control chromosomes. Both had typical demyelinating sensorimotor neuropathy, but the son showed initial symptom onset at age 10, whereas the mother had onset of clinical symptoms in her late fifties.
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Gerding, W. M., Koetting, J., Epplen, J. T., Neusch, C. Hereditary and sensory neuropathy caused by a novel mutation in LITAF. Neuromusc. Disord. 19: 701-703, 2009. [PubMed: 19541485] [Full Text: https://doi.org/10.1016/j.nmd.2009.05.006]
Lee, S. M., Olzmann, J. A., Chin, L. S., Li, L. Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J. Cell Sci. 124: 3319-3331, 2011. [PubMed: 21896645] [Full Text: https://doi.org/10.1242/jcs.087114]
Lee, S. M., Sha, D., Mohammed, A. A., Asress, S., Glass, J. D., Chin, L.-S., Li, L. Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. Hum. Molec. Genet. 22: 1755-1770, 2013. [PubMed: 23359569] [Full Text: https://doi.org/10.1093/hmg/ddt022]
Meggouh, F., de Visser, M., Arts, W. F. M., De Coo, R. I. F. M., van Schaik, I. N., Baas, F. Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. Ann. Neurol. 57: 589-591, 2005. [PubMed: 15786462] [Full Text: https://doi.org/10.1002/ana.20434]
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Saifi, G. M., Szigeti, K., Wiszniewski, W., Shy, M. E., Krajewski, K., Hausmanowa-Petrusewicz, I., Kochanski, A., Reeser, S., Mancias, P., Butler, I., Lupski, J. R. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum. Mutat. 25: 372-383, 2005. [PubMed: 15776429] [Full Text: https://doi.org/10.1002/humu.20153]
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Street, V. A., Goldy, J. D., Golden, A. S., Tempel, B. L., Bird, T. D., Chance, P. F. Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am. J. Hum. Genet. 70: 244-250, 2002. [PubMed: 11713717] [Full Text: https://doi.org/10.1086/337943]
Takashiba, S., Van Dyke, T. E., Shapira, L., Amar, S. Lipopolysaccharide-inducible and salicylate-sensitive nuclear factor(s) on human tumor necrosis factor alpha promoter. Infect. Immun. 63: 1529-1534, 1995. [PubMed: 7890420] [Full Text: https://doi.org/10.1128/iai.63.4.1529-1534.1995]
Tang, X., Metzger, D., Leeman, S., Amar, S. LPS-induced TNA-alpha factor (LITAF)-deficient mice express reduced LPS-induced cytokine: evidence for LITAF-dependent LPS signaling pathways. Proc. Nat. Acad. Sci. 103: 13777-13782, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 104: 3015 only, 2007. [PubMed: 16954198] [Full Text: https://doi.org/10.1073/pnas.0605988103]