Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPK
Cytogenetic location: 9q21.32 Genomic coordinates (GRCh38) : 9:83,968,083-83,980,615 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.32 | Au-Kline syndrome | 616580 | Autosomal dominant | 3 |
HNRNPK is a conserved RNA-binding protein that is involved in multiple processes of gene expression, including chromatin remodeling, transcription, and mRNA splicing, translation, and stability. These multiple functions of HNRNPK reflect its ability to associate with a diverse group of molecular partners (summary by Fukuda et al., 2009).
Dejgaard et al. (1994) identified HNRNPK acidic nuclear proteins using a monoclonal antibody that distinguished between quiescent and proliferating human keratinocytes. At least 4 major HNRNPK proteins (HNRNPK-A, -B, -C, and -D) and their modified forms were present in similar overall levels in quiescent and proliferating normal keratinocytes, although clear differences were observed in levels of some of the individual isoforms. Using a monoclonal antibody as a probe, Dejgaard et al. (1994) cloned a cDNA coding for HNRNPK-B, and this was used to screen for additional clones. Sequencing of positive clones revealed 4 HNRNPK splice variants encoding HNRNPK-A, -B, -C, and -D. The HNRNPK isoforms contain 458 to 464 amino acids and have calculated molecular masses of 50 to 51 kD. The 458-amino acid isoform A contains an N-terminal acidic domain, followed by 2 repeats of about 70 amino acids each, an RGG box, a proline-rich segment, and a third repeat at the C terminus. The 4 proteins resolved in a 2-dimensional gel with apparent molecular masses of 64 to 66 kD and pI from 4.9 to 5.5.
By Northern blot analysis, Fukuda et al. (2009) detected variable Hnrnpk expression in all mouse tissues examined except skeletal muscle. Expression was also detected in 2 mouse and 2 human cell lines.
Poenisch et al. (2015) stated that HNRNPK contains an N-terminal nuclear localization signal, followed by 2 RNA-binding domains, a protein interaction domain, a nuclear shuttling domain, and a C-terminal DNA-binding domain. A C-terminal kinase interaction domain overlaps the nuclear shuttling domain and the DNA-binding domain.
Dejgaard et al. (1994) noted that HNRNPK has been implicated in pre-mRNA metabolism of transcripts containing cytidine-rich sequences. The results of Dejgaard et al. (1994) pointed toward a role in cell cycle progression.
Inoue et al. (2007) found that intracellular anti-HNRNPK compromised cell migration of human fibrosarcoma cells. They found that cytoplasmic accumulation of HNRNPK was crucial for cell migration and metastasis.
Using yeast 2-hybrid assays, Fukuda et al. (2009) found that rat Rbm42 (613232) interacted with human HNRNPK, and mutation analyses revealed that the C-terminal RRM of Rbm42 interacted with the C-terminal KH domain of HNRNPK. Epitope-tagged and endogenous human RBM42 isoforms and HNRNPK coimmunoprecipitated in reciprocal reactions using HEK293 and HeLa cell lysates, and both RBM42 and HNRNPK also independently bound RNA. The isolated C-terminal domains of human RBM42 and HNRNPK interacted in vitro. In vivo, however, RNA appeared to mediate the association of the full-length proteins, since RNase treatment disrupted their interaction. Immunofluorescence microscopy revealed that both proteins predominantly localized in the nucleus of MTD-1A mouse mammary tumor cells. Following cell stress, they independently localized in cytoplasmic stress granules, transient foci that sequester mRNAs of housekeeping genes during cell stress. Depletion of Hnrnpk, but not Rbm42, in MTD-1A cells interfered with the recovery of ATP production following release from cell stress. However, simultaneous Hnrnpk and Rbm42 depletion further reduced cellular ATP levels following release from cell stress. Fukuda et al. (2009) concluded that HNRNPK and RBM42 are involved in the maintenance of cellular ATP levels during stress, possibly by protecting critical mRNAs.
By conducting a comprehensive whole-virus RNA interference-based screen, Poenisch et al. (2015) identified 40 host dependency and 16 host restriction factors, including HNRNPK, involved in entry/replication or assembly/release of hepatitis C virus (HCV; see 609532). HNRNPK suppressed particle production of HCV, but not of Dengue virus (see 614371), without affecting viral RNA replication. Knockdown and rescue experiments revealed that the single-strand RNA-binding domains and the protein-binding domain of HNRNPK were required for suppression of HCV particle production. Interaction of HCV RNA with HNRNPK was specific and was impaired by mutations that reduced the suppression of HCV particle production. In HCV-infected cells, the subcellular distribution of HNRNPK shifted to sites in close proximity to lipid droplets, and HNRNPK colocalized with HCV core protein and HCV plus-strand RNA. Altered HNRNPK distribution did not occur with HNRNPK variants unable to suppress HCV virion formation. Poenisch et al. (2015) concluded that HNRNPK may determine the efficiency of HCV particle production and limit the availability of viral RNA for incorporation into virions.
Sweetser et al. (2005) determined that the HNRNPK gene contains 15 exons.
By genomic sequence analysis, Reddy et al. (2008) found that the first intron of HNRNPK contains the gene for microRNA-7-1 (MIR7-1; 615239).
Dejgaard et al. (1994) mapped the HNRNPK gene to chromosome 9 by Southern blot analysis of human/rodent somatic cell hybrids. Tommerup and Leffers (1996) mapped the HNRNPK gene to chromosome 9q21.32-q21.33 by fluorescence in situ hybridization.
In 2 unrelated boys with Au-Kline syndrome (AUKS; 616580), Au et al. (2015) identified different de novo heterozygous, putative loss-of-function mutations in the HNRNPK gene (600712.0001 and 600712.0002). The mutations were found by exome sequencing. Functional studies of the variants were not performed.
Using trio-based whole-exome sequencing, Lange et al. (2016) identified a de novo heterozygous frameshift mutation in the HNRNPK gene (600712.0003) in a boy (BRC052) with a phenotype consistent with AUKS. The variant, which was confirmed by Sanger sequencing, was expected to result in a loss of function.
By exome sequencing, Miyake et al. (2017) identified a de novo heterozygous missense mutation in the HNRNPK gene (L155P; 600712.0005) in a Japanese boy with AUKS. The variant was confirmed by Sanger sequencing and was not present in the ExAC, Exome Variant Server, or Human Genetic Variation databases or in an in-house database of 575 exomes.
Using whole-exome sequencing, Au et al. (2018) identified 5 patients with AUKS who had de novo heterozygous loss-of-function variants in the HNRNPK gene (see, e.g., 600712.0004). In addition, they reported a girl (patient 10) with a de novo 264-kb microdeletion encompassing 9q21.32, which disrupted HNRNPK as well as 3 additional genes and a microRNA with no known human disease association. The common phenotype between the patients with HNRNPK truncating variants and the microdeletion supported haploinsufficiency of the HNRNPK gene as the pathogenic mechanism of AUKS.
Choufani et al. (2022) reported heterozygous mutations in the HNRNPK gene in a cohort of 32 patients with AUKS, 6 of whom had previously been reported. In the cohort, 13 patients had missense mutations (including E85K (600712.0006), reported in 5 unrelated patients), 8 patients had nonsense mutations, 4 patients had intronic mutations, 3 patients had splicing mutations, 2 patients had frameshift mutations, 1 patient had an in-frame indel, and 1 patient had a large (264 kb) deletion that involved the HNRNPK gene. About 85% of the mutations were clustered in the K homology RNA-binding domain.
In a 4-year-old Japanese boy, born of nonconsanguineous parents, with Okamoto syndrome, Okamoto (2019) identified a de novo heterozygous splice site mutation in the HNRNPK gene (600713.0007). The mutation was found by Sanger sequencing of the HNRNPK gene. Based on the similarity between Okamoto syndrome and AUKS and the finding of mutations in HNRNPK in patients with Okamoto syndrome, these disorders are considered to be identical.
In a 10-year-old girl, born of nonconsanguineous parents, with Okamoto syndrome, Maystadt et al. (2020) identified a de novo heterozygous splice site mutation in the HNRNPK gene (600713.0008). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.
In an 11-year-old girl with AUKS, who was initially thought to have Kabuki syndrome, Dentici et al. (2018) identified a de novo heterozygous mutation 1-bp duplication in the HNRNPK gene (600713.0009). mRNA analysis in patient leukocytes demonstrated lack of expression of the HNRNPK allele with the mutation, indicating that the mutation led to nonsense-mediated decay.
In a 17-year-old boy with Au-Kline syndrome (AUKS; 616580), Au et al. (2015) identified a de novo heterozygous 1-bp duplication (c.953+1dupC, NM_002140.3) in the HNRNPK gene between the +1 and +2 splice sites, which was predicted to alter gene expression either through nonsense-mediated mRNA decay or a frameshift and premature termination (Gly319ArgfsTer6). The mutation was found by exome sequencing, confirmed by Sanger sequencing, and filtered against the dbSNP database.
In an 11-year-old boy with Au-Kline syndrome (AUKS; 616580), Au et al. (2015) identified a de novo heterozygous c.257G-A transition (c.257G-A, NM_002140.3) in the HNRNPK gene. Although the sequence change was predicted to result in an arg86-to-his (R86H) substitution, it occurred in the last codon of exon 5 and was predicted to result in a splice site mutation. Western blot analysis of patient cells showed that the protein was significantly decreased by about 50% compared to controls.
Using trio-based whole-exome sequencing, Lange et al. (2016) identified a de novo heterozygous 2-bp insertion (c.931_932insTT) in exon 11 of the HNRNPK gene in a boy (BRC052) with Au-Kline syndrome (AUKS; 616580). The insertion was predicted to result in a frameshift (Pro31LeufsTer40) two-thirds through the coding sequence and was expected to result in a loss of function. The variant, which was confirmed by Sanger sequencing, was not present in the ExAC or 1000 Genomes Project databases.
In a 9-year-old boy with Au-Kline syndrome (AUKS; 616580), Au et al. (2018) identified a de novo heterozygous 1-bp duplication (c.779dupG, NM_002140.4) in the HNRNPK gene, resulting in an asp262-to-ter (D262X) substitution that was predicted to result in a loss of function. The mutation, which was found by trio-based whole-exome sequencing, was confirmed by Sanger sequencing.
In a 4-year-old Japanese boy with Au-Kline syndrome (AUKS; 616580), Miyake et al. (2017) identified de novo heterozygosity for a c.464T-C transition (c.464T-C, NM_002140.4) in the HNRNPK gene, resulting in a leu155-to-pro (L155P) substitution at a highly conserved residue. Structural modeling showed that the mutation occurs in the first turn of helix alpha-1, suggesting that it affects a hydrophobic core packing involving the side chain of L155 and stability of helix alpha-1, thereby impairing the interaction of the protein with DNA or RNA. The variant was confirmed by Sanger sequencing and was not present in the ExAC, Exome Variant Server, or Human Genetic Variation databases or in an in-house database of 575 exomes.
In 5 unrelated patients with Au-Kline syndrome (AUKS; 616580), Choufani et al. (2022) identified a de novo heterozygous c.253G-A transition (c.253G-A, NM_002140.4) in exon 6 of the HNRNPK gene, resulting in a glu85-to-lys (E85K) substitution. In 3 patients who were tested, an intermediate AUKS-specific DNA methylation signature was identified in patient blood.
In a 4-year-old Japanese boy, born of nonconsanguineous parents, with Okamoto syndrome (AUKS; 616580), Okamoto (2019) identified a de novo heterozygous splice site mutation in intron 16 of the HNRNPK gene. The mutation was found by Sanger sequencing of the HNRNPK gene.
In a patient with Okamoto syndrome (AUKS; 616580), Maystadt et al. (2020) identified de novo heterozygosity for a c.257+5G-A transition (c.257+5G-A, NM_002140.4) in intron 6 of the HNRNPK gene, predicted to result in a frameshift and premature termination (Ile87TyrfsTer12). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. rDNA analysis in blood from the patient demonstrated that the c.257+5G-A mutation resulted in use of an intronic cryptic splicing site and a transcript with retention of 49 intronic nucleotides.
In a patient with Au-Kline syndrome (AUKS; 616580), Dentici et al. (2018) identified a de novo heterozygous 1-bp duplication (c.998dupA) in the HNRNPK gene, resulting in a tyr333-to-ter (Y333X) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. mRNA analysis in patient leukocytes demonstrated lack of expression of the HNRNPK allele with the c.998dupA mutation, indicating that the mutation led to nonsense-mediated decay.
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Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D. GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK. Hum. Mutat. 36: 1009-1014, 2015. [PubMed: 26173930] [Full Text: https://doi.org/10.1002/humu.22837]
Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. Am. J. Hum. Genet. 109: 1867-1884, 2022. [PubMed: 36130591] [Full Text: https://doi.org/10.1016/j.ajhg.2022.08.014]
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Dentici, M. L., Barresi, S., Niceta, M., Pantaleoni, F., Pizzi, S., Dallapiccola, B., Tartaglia, M., Digilio, M. C. Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency. Clin. Genet. 93: 401-407, 2018. [PubMed: 28374925] [Full Text: https://doi.org/10.1111/cge.13029]
Fukuda, T., Naiki, T., Saito, M., Irie, K. hnRNP K interacts with RNA binding motif protein 42 and functions in the maintenance of cellular ATP level during stress conditions. Genes Cells 14: 113-128, 2009. [PubMed: 19170760] [Full Text: https://doi.org/10.1111/j.1365-2443.2008.01256.x]
Inoue, A., Sawata, S. Y., Taira, K., Wadhwa, R. Loss-of-function screening by randomized intracellular antibodies: identification of hnRNP-K as a potential target for metastasis. Proc. Nat. Acad. Sci. 104: 8983-8988, 2007. [PubMed: 17483488] [Full Text: https://doi.org/10.1073/pnas.0607595104]
Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U. A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia. Clin. Genet. 90: 258-262, 2016. [PubMed: 26954065] [Full Text: https://doi.org/10.1111/cge.12773]
Maystadt, I., Deprez, M., Moortgat, S., Benoit, V., Karadurmus, D. A second case of Okamoto syndrome caused by HNRNPK mutation. Am. J. Med. Genet. 182A: 1537-1539, 2020. [PubMed: 32222014] [Full Text: https://doi.org/10.1002/ajmg.a.61568]
Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N. A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter) Clin. Genet. 92: 554-555, 2017. [PubMed: 28771707] [Full Text: https://doi.org/10.1111/cge.13023]
Okamoto, N. Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation. Am. J. Med. Genet. 179A: 822-826, 2019. [PubMed: 30793470] [Full Text: https://doi.org/10.1002/ajmg.a.61079]
Poenisch, M., Metz, P., Blankenburg, H., Ruggieri, A., Lee, J.-Y., Rupp, D., Rebhan, I., Diederich, K., Kaderali, L., Domingues, F. S., Albrecht, M., Lohmann, V., Erfle, H., Bartenschlager, R. Identification of HNRNPK as regulator of hepatitis C virus particle production. PLoS Pathog. 11: e1004573, 2015. [PubMed: 25569684] [Full Text: https://doi.org/10.1371/journal.ppat.1004573]
Reddy, S. D. N., Ohshiro, K., Rayala, S. K., Kumar, R. MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its function. Cancer Res. 68: 8195-8200, 2008. [PubMed: 18922890] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-2103]
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Tommerup, N., Leffers, H. Assignment of human KH-box-containing genes by in situ hybridization: HNRNPK maps to 9q21.32-q21.33, PCBP1 to 2p12-p13, and PCBP2 to 12q13.12-q13.13, distal to FRA12A. Genomics 32: 297-298, 1996. [PubMed: 8833161] [Full Text: https://doi.org/10.1006/geno.1996.0121]