Alternative titles; symbols
HGNC Approved Gene Symbol: IPO8
Cytogenetic location: 12p11.21 Genomic coordinates (GRCh38) : 12:30,628,988-30,695,869 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.21 | VISS syndrome | 619472 | Autosomal recessive | 3 |
RAN (601179) is a Ras-related small GTP-binding protein that plays a key role in nuclear localization signal (NLS)-dependent protein import. By searching EST databases for sequences homologous to the Xenopus Ran-binding protein RanBP7 (605586), Gorlich et al. (1997) identified a Ran-binding protein that they designated RANBP8 and cloned the cDNA from a HeLa cDNA library. Human RANBP8 and Xenopus RanBP7 share 61% amino acid identity. They both belong to a Ran-binding protein superfamily whose members share with importin-beta (602738) an N-terminal sequence motif that appears to account for RanGTP binding.
Weinmann et al. (2009) found that epitope-tagged IPO8 localized to the nucleus and to cytoplasmic RNA processing bodies (P bodies) and stress granules in transfected human embryonic kidney cells.
Ziegler et al. (2021) stated that the IPO8 gene encodes a 1,037-amino acid protein with an N-terminal beta-importin domain (amino acids 22-102) and a CSE1-like domain (amino acids 202-441) containing a RanGTPase-binding motif characteristic of beta-importins.
Ziegler et al. (2021) stated that the IPO8 gene contains 25 exons.
Stumpf (2021) mapped the IPO8 gene to chromosome 12p11.21 based on an alignment of the IPO8 sequence (GenBank BC167853) with the genomic sequence (GRCh38).
By fluorescence labeling in Xenopus, Gorlich et al. (1997) showed that RanBP8 bound to the nuclear pore complex. Like importin-beta and RanBP7, RanBP8 formed a trimeric complex with RanGTP (602362) and RANBP1 (601180) and inhibited the GAP stimulation of the Ran GTPase.
Using protein pull-down assays and immunoprecipitation analysis, Weinmann et al. (2009) found that IPO8 interacted in an RAN-dependent manner with argonaute (AGO) proteins, which are involved in microRNA (miRNA) processing and function. Knockdown of IMP8 in HeLa or HEK293 cells resulted in redistribution of AGO2 (EIF2C2; 606229) from the nucleus to the cytoplasm. IPO8 was required for AGO2 binding to a large set of target mRNAs, and knockdown of IPO8 led to a moderate increase of target mRNAs. Knockdown of IPO8 had no effect on AGO stability, miRNA biogenesis, or miRNA loading onto AGO proteins. Weinmann et al. (2009) concluded that IPO8 is required for miRNA-guided gene silencing and affects nuclear localization of AGO proteins.
In 6 unrelated probands with early-onset vascular aneurysm, skeletal anomalies, and skin and joint laxity (VISS syndrome; 619472), Van Gucht et al. (2021) identified homozygosity or compound heterozygosity for truncating mutations in the IPO8 gene (see, e.g., 605600.0001-605600.0004) that segregated with disease in the respective families and were not found in the gnomAD database or were present at very low minor allele frequency.
In 12 patients from 9 families with VISS syndrome, Ziegler et al. (2021) reported biallelic missense or truncating mutations in the IPO8 gene (see, e.g., 605600.0002 and 605600.0005-605600.0006) that segregated with disease and were not found in the gnomAD database or were present at very low minor allele frequency.
By combining exome/genome sequencing with data repository analysis, Bertoli-Avella et al. (2021) identified 9 unrelated patients with VISS syndrome and mutations in the IPO8 gene (see, e.g., 605600.0001 and 605600.0007).
Van Gucht et al. (2021) studied Ipo8 -/- mice by serial transthoracic echocardiography from age 4 weeks to 32 weeks and observed statistically significant dilatation of the aortic root and the distal ascending aorta in mutant mice compared to controls, with aneurysms of the distal ascending aorta visible at the age of 8 to 12 weeks. Aortic root enlargement was present in both mutant males and females, but ascending aortic aneurysm was very pronounced and statistically significant only in mutant males. Animals were kept alive until 48 weeks of age, during which time 3 homozygous mutant males died from aortic rupture, whereas no rupture-related mortality was observed in homozygous mutant females or wildtype mice. Compliance assays suggested augmented passive stiffness of the ascending aorta in male Ipo8-null mice throughout life. Immunohistologic investigation of mutant aortic walls revealed elastic fiber disorganization and fragmentation along with a signature of increased TGF-beta (190180) signaling, as evidenced by nuclear phosphorylated Smad2 (601366) accumulation. RT-qPCR assays of the aortic wall in mutant males demonstrated decreased Smad6 (602931)/7 (602932) and increased Mmp2 (120360) and Ccn2 (121009) expression, supporting a role for dysregulation of the TGF-beta signaling pathway in development of thoracic aortic aneurysms.
Ziegler et al. (2021) generated ipo8 -/- zebrafish and observed embryos that were ovoid rather than round, with a tail bud that failed to extend around the yolk, resulting in elongated pear-shaped embryos. These morphologic changes correlated with an increased death rate. As development proceeded, a range of tail elongation defects became apparent, and by 3 days postfertilization (dpf), most embryos developed cardiac edema. Analysis of heart and vessel morphology at 2 dpf revealed severe defects in heart chamber formation, with atrial and ventricular chambers being less or not delimited in ipo8 -/- mutants. The mutants also exhibited arteriovenous malformations in the head as well as abnormal arteriovenious connections in the dorsal midline junction, and poorly differentiated central arteries that appeared irregular, thin, and poorly lumenized. By 3 dpf, in addition to heart edema, there were blood vessel patterning abnormalities that resulted in absent or abnormal blood flow in the tail region. Ziegler et al. (2021) noted that early dorsoventral patterning defects are a telltale sign of altered TGFB/BMP (see 112264) signaling, and they detected significantly reduced nuclear localization of phosphorylated Smad1 (601595)/5 (603110)/9 (603295). Pathway enrichment analysis revealed that genes differentially regulated upon ipo8 depletion encode multiple components of the TGFB/BMP pathway as well as genes involved in angiotensin (see 106150)/angiogenesis pathways. Expression of smad7, a direct transcriptional target of the TGFB/BMP pathway, was strongly decreased in ipo8 -/- embryos compared to wildtype at 13 and 24 hpf. The authors concluded that importin-8 plays a critical role during the early stage of development by controlling phosphorylated Smad nuclear translocation and downstream TGFB/BMP-dependent transcription, and that the model supports a causative role for IPO8 deficiency in the vascular and skeletal defects observed in affected individuals.
In 2 Saudi-Arabian brothers (family 4), ages 6 years and 10 years, with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified homozygosity for a c.776G-A transition (c.776G-A, NM_006390.3) in the IPO8 gene, resulting in a trp259-to-ter (W259X) substitution. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database.
In 3 unrelated patients (patients 8, 9, and 12) with VISS syndrome, Bertoli-Avella et al. (2021) identified homozygosity for the W259X mutation in the IPO8 gene. Familial segregation was not reported.
In a 19-year-old man (family 6) with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified homozygosity for a splicing mutation (c.2900-1G-A, NM_006390.3) in the IPO8 gene, predicted to result in a deletion/insertion (Thr967_Glu1006delinsLys). His unaffected first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database.
In a 33-year-old Australian woman (family 7, patient I-10) with VISS syndrome, Ziegler et al. (2021) identified compound heterozygosity for the c.2900-1G-A splicing mutation in intron 23 of the IPO8 gene, and a 1-bp deletion (c.2279delT; 605600.0005), causing a frameshift predicted to result in a premature termination codon (Leu760ProfsTer10) in the IPO8 gene. Her unaffected parents were each heterozygous for 1 of the mutations. The 1-bp deletion was present at very low frequency in the gnomAD database (1.06 x 10(-5), no homozygotes).
In an 8-year-old girl (family 3) with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified compound heterozygosity for a splicing mutation (c.1428+5G-A, NM_006390.3) in intron 12 of the IPO8 gene, causing skipping of exon 13 and a predicted in-frame deletion of 30 amino acids (Lys447_Arg476del), and a 5-bp deletion (c.2597_2601delTTTTC; 605600.0004), causing a frameshift predicted to result in an premature termination codon (Leu866ProfsTer12). Her unaffected parents were each heterozygous for 1 of the mutations. The splicing mutation was not found in the gnomAD database, whereas the 5-bp deletion was present at very low minor allele frequency (1 of 250,920 alleles). Analysis of cDNA from puromycin-treated and untreated patient fibroblasts indicated that the 5-bp mutation results in nonsense-mediated decay; Sanger sequencing of the RT-PCR produced from blood-derived cDNA confirmed in-frame skipping of exon 13 with the splicing mutation.
For discussion of the 5-bp deletion (c.2597_2601delTTTTC, NM_006390.3) in the IPO8 gene that was found in compound heterozygous state in an 8-year-old girl (family 3) with VISS syndrome (VISS; 619472) by Van Gucht et al. (2021), see 605600.0003.
For discussion of the 1-bp deletion (c.2279delT, NM_006390.3) in the IPO8 gene, causing a frameshift predicted to result in an premature termination codon (Leu760ProfsTer10), that was found in compound heterozygous state in an 8-year-old Australian girl (family 7, patient I-10) with VISS syndrome (VISS; 619472) by Ziegler et al. (2021), see 605600.0002.
In an Ashkenazi brother and sister (family 1, patients I-1 and I-2) with VISS syndrome (VISS; 619472), Ziegler et al. (2021) identified homozygosity for a c.262G-A transition (c.262G-A, NM_006390.3) in the IPO8 gene, resulting in an asp88-to-asn (D88N) substitution at a highly conserved residue within the N-terminal domain. Their unaffected sister was heterozygous for the mutation, which was not found in the gnomAD database; DNA was unavailable from their deceased consanguineous parents. Immunoblot analysis of protein lysates from patient fibroblasts showed a striking reduction in IPO8 compared to control.
In 2 unrelated patients (patients 7 and 11) with VISS syndrome (VISS; 619472), Bertoli-Avella et al. (2021) identified homozygosity for a 5-bp deletion (c.2695+4_2695+8del) in the IPO8 gene. Familial segregation and functional analysis were not reported.
Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders. Genet. Med. 23: 1551-1568, 2021. [PubMed: 33875846] [Full Text: https://doi.org/10.1038/s41436-021-01159-0]
Gorlich, D., Dabrowski, M., Bischoff, F. R., Kutay, U., Bork, P., Hartmann, E., Prehn, S., Izaurralde, E. A novel class of RanGTP binding proteins. J. Cell Biol. 138: 65-80, 1997. [PubMed: 9214382] [Full Text: https://doi.org/10.1083/jcb.138.1.65]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/05/2021.
Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. Am. J. Hum. Genet. 108: 1115-1125, 2021. [PubMed: 34010605] [Full Text: https://doi.org/10.1016/j.ajhg.2021.04.019]
Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G. Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs. Cell 136: 496-507, 2009. [PubMed: 19167051] [Full Text: https://doi.org/10.1016/j.cell.2008.12.023]
Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation. Am. J. Hum. Genet. 108: 1126-1137, 2021. [PubMed: 34010604] [Full Text: https://doi.org/10.1016/j.ajhg.2021.04.020]