Alternative titles; symbols
HGNC Approved Gene Symbol: TPR
Cytogenetic location: 1q31.1 Genomic coordinates (GRCh38): 1:186,311,652-186,375,253 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.1 | ?Intellectual developmental disorder, autosomal recessive 79 | 620393 | Autosomal recessive | 3 |
The TPR gene encodes a structural component of the nuclear basket, which is a component of the nuclear pore complex. Nuclear pore complexes are nuclear envelope channels that regulate the trafficking of macromolecules between the nucleus and cytoplasm. TPR and associated proteins play a role in transcriptional regulation and mRNA export (summary by Van Bergen et al., 2022).
The TPR locus, which maps to chromosome 1, expresses a 10-kb RNA in all human cell lines tested (Dean et al., 1985). In a cell line rendered tumorigenic with the direct-acting carcinogen N-methyl-N-prime-nitronitrosoguanidine (MNNG), Dean et al. (1987) defined an activated MET oncogene that expresses a novel 5.0-kb RNA transcript which is a hybrid RNA derived from a DNA rearrangement involving the TPR locus and the MET locus (on 7q; 164860). Although most of the hybrid RNA is derived from the MET oncogene, the 5-prime portion uses some exons from the TPR gene, presumably the promoter region. Oncogenic activation of MET is reminiscent of the Philadelphia chromosomal translocation in chronic myeloid leukemia that generates the hybrid BCR/ABL tyrosine kinase p210 (see 151410).
Gonzatti-Haces et al. (1988) identified the proteins encoded by the human TPR-MET oncogene and the human MET protooncogene.
By fluorescence in situ hybridization, Miranda et al. (1994) assigned the TPR gene to chromosome 1q25.
In 2 sibs, born of unrelated Maltese parents, with autosomal recessive intellectual developmental disorder-79 (MRT79; 620393), Van Bergen et al. (2022) identified compound heterozygous mutations in the TPR gene: a nonsense mutation (R2209X; 189940.0001) and a splice site mutation (189940.0002). The mutations, which were found by whole-genome sequencing, were each inherited from the unaffected parents; both mutations were absent from the gnomAD database. The findings were consistent with a loss-of-function effect, but the authors suggested that some residual function conferred by the splice site mutation may still exist. Patient fibroblasts showed decreased expression of the TPR protein and decreased density of TPR-containing nuclear pores in the nuclear envelope. The total intensity of mRNA in the nucleus was significantly reduced compared to controls, although cytoplasmic mRNA levels were unchanged. The findings suggested that depletion of TPR may cause defects in transcription with downstream effects on mRNA export.
In 2 sibs, born of unrelated Maltese parents, with autosomal recessive intellectual developmental disorder-79 (MRT79; 620393), Van Bergen et al. (2022) identified compound heterozygous mutations in the TPR gene: a c.6625C-T transition (c.6625C-T, NM_003292.2) in exon 47, resulting in an arg2209-to-ter (R2209X) substitution, and a G-to-A transition in intron 20 (c.2610+5G-A; 189940.0002), resulting in a splicing defect. The mutations, which were found by whole-genome sequencing, were each inherited from the unaffected parents; neither mutation was present in the gnomAD database. Analysis of patient cells showed that the R2209X mutation resulted in nonsense-mediated mRNA decay, and that the splice site mutation caused an in-frame deletion of 12 highly conserved amino acids that form part of the coiled-coil domain. The splice site mutation was predicted to cause a destabilizing effect on the protein. The findings were consistent with a loss-of-function effect, but the authors suggested that some residual function conferred by the splice site mutation may still exist. Patient fibroblasts showed decreased expression of the TPR protein and decreased density of TPR-containing nuclear pores in the nuclear envelope. There was also an increase in nuclear pore complex density compared to controls, suggesting a compensatory effect. The total intensity of mRNA in the nucleus was significantly reduced compared to controls, although cytoplasmic mRNA levels were unchanged. The findings suggested that depletion of TPR may cause defects in transcription with downstream effects on mRNA export.
For discussion of the G-to-A transition in intron 20 of the TPR gene (c.2610+5G-A, NM_003292.2), resulting in a splicing defect, that was found in compound heterozygous state in 2 sibs with autosomal recessive intellectual developmental disorder-79 (MRT79; 620393) by Van Bergen et al. (2022), see 189940.0001.
Dean, M., Park, M., Le Beau, M. M., Robins, T. S., Diaz, M. O., Rowley, J. D., Blair, D. G., Vande Woude, G. F. The human MET oncogene is related to the tyrosine kinase oncogenes. Nature 318: 385-388, 1985. [PubMed: 4069211] [Full Text: https://doi.org/10.1038/318385a0]
Dean, M., Park, M., Vande Woude, G. F. Characterization of the rearranged TPR-MET oncogene breakpoint. Molec. Cell. Biol. 7: 921-924, 1987. [PubMed: 3821733] [Full Text: https://doi.org/10.1128/mcb.7.2.921-924.1987]
Gonzatti-Haces, M., Seth, A., Park, M., Copeland, T., Oroszlan, S., Vande Woude, G. F. Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. Proc. Nat. Acad. Sci. 85: 21-25, 1988. [PubMed: 3277171] [Full Text: https://doi.org/10.1073/pnas.85.1.21]
Miranda, C., Minoletti, F., Greco, A., Sozzi, G., Pierotti, M. A. Refined localization of the human TPR gene to chromosome 1q25 by in situ hybridization. Genomics 23: 714-715, 1994. [PubMed: 7851906] [Full Text: https://doi.org/10.1006/geno.1994.1566]
Van Bergen, N. J., Bell, K. M., Carey, K., Gear, R., Massey, S., Murrell, E. K., Gallacher, L., Pope, K., Lockhart, P. J., Kornberg, A., Pais, L., Walkiewicz, M., Simons, C., MCRI Rare Diseases Flagship, Wickramasinghe, V. O., White, S. M., Christodoulou, J. Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans. Hum. Molec. Genet. 31: 362-375, 2022. [PubMed: 34494102] [Full Text: https://doi.org/10.1093/hmg/ddab248]