Alternative titles; symbols
HGNC Approved Gene Symbol: TNPO2
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38) : 19:12,699,201-12,723,932 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies | 619556 | Autosomal dominant | 3 |
Transportin-2 (TNPO2) mediates multiple pathways, including nonclassical nucleocytoplasmic shuttling of developmental and neuronal proteins, and its activity is dependent on the RAN GTP/GDP gradient (summary by Goodman et al., 2021).
Transportin-1 (KPNB2; 602901) interacts directly and specifically with M9, the bidirectional transport signal of the nuclear shuttling protein hnRNPA1 (164017) and mediates hnRNPA1 nuclear import. In the course of isolating additional transportin-1 cDNAs, Siomi et al. (1997) isolated cDNAs encoding a related protein that they designated 'transportin-2.' The sequence of the predicted 894-amino acid protein shares 84% identity with that of transportin-1. One notable difference is that transportin-2 contains a short extra sequence within the region corresponding to the M9-interacting domain of transportin-1. Far Western blotting showed that transportin-2 and transportin-1 have different substrate specificities. Siomi et al. (1997) suggested that the insert in transportin-2 modifies its interaction with import substrates.
Transport of macromolecules between the cell nucleus and cytoplasm occurs through the nuclear pores and is mediated by soluble carriers known as karyopherins, transportins, importins, or exportins. Shamsher et al. (2002) found that transportin-2 forms complexes with the mRNA export factor TAP (NXF1; 602647) that strictly depend on the presence of RanGTP. The data supported the conclusion that transportin-2 participates directly in the export of a large proportion of cellular mRNAs, and that TAP connects transportin-2 to mRNAs to be exported.
Stumpf (2021) mapped the TNPO2 gene to chromosome 19p13.13 based on an alignment of the TNPO2 sequence (GenBank AF019039) with the genomic sequence (GRCh38).
In 15 unrelated patients with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified 15 different heterozygous mutations in the TNPO2 gene (see, e.g., 603002.0001-603007.0005). The patients were gathered through international collaboration, and the mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing (except for 1). None were present in the gnomAD database. All but one of the mutations occurred de novo; 1 was inherited from a mother who was low-level mosaic for the variant. Most of the mutations were missense and distributed throughout the gene, but there were 2 small intragenic in-frame insertion/deletions. Functional studies of patient cells were not performed, but expression of variant cDNA of 6 of the mutations in Drosophila showed that they were unable to rescue the developmental defects in tnpo-null flies despite normal protein levels (see ANIMAL MODEL). In addition, overexpression of 3 of the variants (G28R, D156N, and A546V) caused significant developmental toxicity, consistent with a gain-of-function effect. There was some variable expressivity and incomplete penetrance, suggesting variant-specific effects. Studies of another variant (W727C) suggested a loss-of-function effect. Overall, these observations suggested a pleiotropic effect, consistent with the phenotypic variability, although the precise mechanism remained to be determined. Given the role of the gene in cytoplasmic-nuclear cargo shuttling, Goodman et al. (2021) postulated that impaired TNPO2 function disrupts multiple pathways important for development and neuronal maintenance, including ciliogenesis, mitotic spindle assembly, and nuclear envelope assembly. Upregulation of the gene may cause an accumulation of the protein intracellularly, resulting in associated toxicity.
Goodman et al. (2021) found that knockdown of the Drosophila tnpo gene using mutant alleles or RNAi caused dose-dependent developmental abnormalities, including abnormal eye and wing development and embryonic lethality. The eyes were smaller and rough with disorganized ommatidia, and the wings showed notches and blisters. Drosophila tnpo was expressed in neuronal cell bodies of the mushroom body in the brain and in the ventral nerve cord. Loss of tnpo expression in neurons impaired synaptic function. Overexpression of the wildtype gene caused similar developmental abnormalities, consistent with a toxic effect, although there were subtle differences. The findings indicated that tnpo is expressed in multiple tissues and is essential for basic development, particularly of the nervous system.
In a 6-year-old girl (patient 1) with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified a de novo heterozygous c.83A-G transition (c.83A-G, NM_001136196.1) in the TNPO2 gene, resulting in a gln28-to-arg (Q28R) substitution at a conserved residue in the N-terminal RAN-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant in Drosophila resulted in developmental defects, including lethality, consistent with a gain-of-function effect.
In a 4-year-old boy (patient 6) with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified a de novo heterozygous c.466G-A transition (c.466G-A, NM_001136196.1) in the TNPO2 gene, resulting in a asp156-to-asn (D156N) substitution at a conserved residue in the N-terminal RAN-binding domain. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Expression of the variant in Drosophila resulted in developmental defects, including lethality, consistent with a gain-of-function effect.
In a 10-year-old girl (patient 7) with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified a de novo heterozygous c.1108T-C transition (c.1108T-C, NM_001136196.1) in the TNPO2 gene, resulting in a trp370-to-arg (W370R) substitution at a conserved residue in the acidic loop domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
In an 8-year-old boy (patient 8) with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified a de novo heterozygous c.1110G-C transversion (c.1110G-C, NM_001136196.1) in the TNPO2 gene, resulting in a trp370-to-cys (W370C) substitution at a conserved residue in the acidic loop domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
In an 9-year-old boy (patient 11) with intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; 619556), Goodman et al. (2021) identified a de novo heterozygous c.1637C-T transition (c.1637C-T, NM_001136196.1) in the TNPO2 gene, resulting in an ala546-to-val (A546V) substitution at a conserved residue in the cargo-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant in Drosophila resulted in developmental defects, including lethality, consistent with a gain-of-function effect.
Goodman, L. D., Cope, H., Nil, Z., Ravenscroft, T. A., Charng, W.-L., Lu, S., Tien, A.-C., Pfundt, R., Koolen, D. A., Haaxma, C. A., Veenstra-Knol, H. E., Wassink-Ruiter, J. S. K., and 36 others. TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila. Am. J. Hum. Genet. 108: 1669-1691, 2021. [PubMed: 34314705] [Full Text: https://doi.org/10.1016/j.ajhg.2021.06.019]
Shamsher, M. K., Ploski, J., Radu, A. Karyopherin beta-2B participates in mRNA export from the nucleus. Proc. Nat. Acad. Sci. 99: 14195-14199, 2002. [PubMed: 12384575] [Full Text: https://doi.org/10.1073/pnas.212518199]
Siomi, M. C., Eder, P. S., Kataoka, N., Wan, L., Liu, Q., Dreyfuss, G. Transportin-mediated nuclear import of heterogeneous nuclear RNP proteins. J. Cell Biol. 138: 1181-1192, 1997. [PubMed: 9298975] [Full Text: https://doi.org/10.1083/jcb.138.6.1181]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/11/2021.