Alternative titles; symbols
HGNC Approved Gene Symbol: TNPO3
SNOMEDCT: 719989007;
Cytogenetic location: 7q32.1 Genomic coordinates (GRCh38): 7:128,954,185-129,056,193 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q32.1 | Muscular dystrophy, limb-girdle, autosomal dominant 2 | 608423 | Autosomal dominant | 3 |
TNPO3 is a nuclear import receptor for serine/arginine-rich (SR) proteins, which are essential precursor-mRNA splicing factors (Kataoka et al., 1999).
Using the RS domain of ASF/SF2 (SFRS1; 600812) as bait in a yeast 2-hybrid screen, followed by screening a HeLa cell cDNA library, Kataoka et al. (1999) cloned TNPO3, which they designated TRNSR. The deduced 975-amino acid protein has a calculated molecular mass of 109.8 kD. It shows significant similarity to other importin-beta/transportin family members (e.g., TNPO1, 602901), including a region required for RanGTP (see RAN; 601179) binding.
By yeast 2-hybrid analysis using the RS domain of the E2 protein of human papillomavirus (HPV)-5 as bait, Lai et al. (2000) cloned a TNPO3 splice variant, TRNSR2, from a HeLa cell cDNA library. The deduced 923-amino acid TRNSR2 protein lacks 2 regions of about 30 amino acids each found in the TRNSR protein identified by Kataoka et al. (1999). Northern blot analysis detected ubiquitous expression of a 4.5-kb transcript, with highest expression in testis. Epitope-tagged TRNSR2 localized throughout transfected HeLa cells, but a mutant lacking the N-terminal region colocalized with splicing factor SC35 (SFRS2; 600813) in nuclear speckles.
Gross (2017) mapped the TNPO3 gene to chromosome 7q32.1 based on an alignment of the TNPO3 sequence (GenBank AJ133769) with the genomic sequence (GRCh38).
Using in vitro binding assays, Kataoka et al. (1999) found that TRNSR bound the RS domains of ASF/SF2 and SC35 directly, but it did not interact with other protein domains examined. A Ran mutant mimicking RanGTP, which promotes dissociation of import receptor-cargo complexes, abolished binding of TRNSR to RS domains. In an in vitro import assay, TRNSR efficiently imported the RS domains of ASF/SF2 and SC35 into the nucleus in an ATP- and RanGDP-dependent manner. Far Western blot analysis showed that TRNSR bound several proteins within an SR protein fraction purified from HeLa nuclear extracts.
Using yeast 2-hybrid analysis, Lai et al. (2000) showed that TRNSR2 interacted with the RS domain in the hinge region of HPV-5 E2. The C-terminal 400 amino acids of TRNSR2 also interacted with ASF/SF2, SC35, and TRA2-beta (SFRS10; 602719). Mutation analysis confirmed that TRNSR2 interacted with the N-terminal RS domain of TRA2-beta, but not with the RNA-binding domains of ASF and TRA2-beta. In vitro pull-down assays revealed that only ASF containing phosphorylated RS domains interacted with TRNSR2 in HeLa cell extracts. Lai et al. (2000) concluded that TRNSR2 has a role in cellular trafficking of phosphorylated SR proteins.
Using a large-scale small interfering RNA screen to identify host factors required by human immunodeficiency virus (HIV)-1 (see 609423), Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. Depletion of the HDF TNPO3, a karyopherin, resulted in HIV inhibition after reverse transcription, but before integration. Brass et al. (2008) proposed that targeting of HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation.
Autosomal Dominant Limb-Girdle Muscular Dystrophy 2
Independently and simultaneously, Melia et al. (2013) and Torella et al. (2013) identified a heterozygous mutation in the TNPO3 gene (610032.0001) in affected members of a large Spanish family with autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2; 608423), earlier designated LGMD1F. The mutation, which was identified by whole-genome sequencing (Melia et al., 2013) and whole-exome sequencing (Torella et al., 2013), segregated with the disorder in the family, which was originally reported by Gamez et al. (2001).
Torella et al. (2013) identified a heterozygous missense mutation in the TNPO3 gene (R818P; 610032.0002) in 1 of 64 additional individuals with sporadic LGMD who were screened using a next-generation sequencing approach.
Associations Pending Confirmation
For discussion of a possible association between variation in the TNPO3 gene and primary biliary cirrhosis, see PBC4 (614220).
In affected members of a large Spanish family with autosomal dominant limb-girdle muscular dystrophy type 1F (LGMDD2; 608423), originally reported by Gamez et al. (2001), Melia et al. (2013) identified a heterozygous 1-bp deletion (c.2771A) in the TAG termination codon of the TNPO3 gene, resulting in extension of the reading frame by 15 codons downstream (Ter924CysextTer15). The mutation, which was identified by whole-genome sequencing, segregated with all 29 affected individuals in the family and was not present in 20 unaffected relatives. The mutation was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, or in over 200 Spanish control alleles. Analysis of patient skeletal muscle cells showed that the mutant mRNA was expressed along with the wildtype protein. Immunostaining of patient muscle showed TNPO3 nuclear staining, but it was unevenly distributed and often limited to the periphery of nuclei compared to control muscle. Melia et al. (2013) postulated a dominant-negative toxic effect.
Independently and simultaneously, Torella et al. (2013) identified the same heterozygous frameshift mutation in affected members of the large Spanish family reported by Gamez et al. (2001). 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 the dbSNP (build 137) database. Transfection of the mutation into HeLa cells showed that the mutant protein was localized around the periphery of the nucleus, whereas wildtype TNPO3 entered the nucleus.
In a patient with sporadic occurrence of limb-girdle muscular dystrophy type 1F (LGMDD2; 608423), Torella et al. (2013) identified a heterozygous c.2453G-A transition in exon 21 of the TNPO3 gene, resulting in an arg818-to-pro (R818P) substitution at a highly conserved residue. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, in 150 in-house control exomes, or in the patient's unaffected sister. Functional studies of the R818P variant were not performed.
Brass, A. L., Dykxhoorn, D. M., Benita, Y., Yan, N., Engelman, A., Xavier, R. J., Lieberman, J., Elledge, S. J. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319: 921-926, 2008. [PubMed: 18187620] [Full Text: https://doi.org/10.1126/science.1152725]
Gamez, J., Navarro, C., Andreu, A. L., Fernandez, J. M., Palenzuela, L., Tejeira, S., Fernandez-Hojas, R., Schwartz, S., Karadimas, C., DiMauro, S., Hirano, M., Cervera, C. Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation. Neurology 56: 450-454, 2001. [PubMed: 11222786] [Full Text: https://doi.org/10.1212/wnl.56.4.450]
Gross, M. B. Personal Communication. Baltimore, Md. 6/13/2017.
Kataoka, N., Bachorik, J. L., Dreyfuss, G. Transportin-SR, a nuclear import receptor for SR proteins. J. Cell Biol. 145: 1145-1152, 1999. [PubMed: 10366588] [Full Text: https://doi.org/10.1083/jcb.145.6.1145]
Lai, M.-C., Lin, R.-I., Huang, S.-Y., Tsai, C.-W., Tarn, W.-Y. A human importin-beta family protein, transportin-SR2, interacts with the phosphorylated RS domain of SR proteins. J. Biol. Chem. 275: 7950-7957, 2000. [PubMed: 10713112] [Full Text: https://doi.org/10.1074/jbc.275.11.7950]
Melia, M. J., Kubota, A., Ortolano, S., Vilchez, J. J., Gamez, J., Tanji, K., Bonilla, E., Palenzuela, L., Fernandez-Cadenas, I., Pristoupilova, A., Garcia-Arumi, E., Andreu, A. L., Navarro, C., Hirano, M., Marti, R. Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain 136: 1508-1517, 2013. [PubMed: 23543484] [Full Text: https://doi.org/10.1093/brain/awt074]
Torella, A., Fanin, M., Mutarelli, M., Peterle, E., Del Vecchio Blanco, F., Rispoli, R., Savarese, M., Garofalo, A., Piluso, G., Morandi, L., Ricci, G., Siciliano, G., Angelini, C., Nigro, V. Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One 8: e63536, 2013. Note: Electronic Article. [PubMed: 23667635] [Full Text: https://doi.org/10.1371/journal.pone.0063536]