Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPA1
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:54,280,726-54,287,087 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 | 615424 | Autosomal dominant | 3 |
| ?Myopathy, distal, 3 | 610099 | Autosomal dominant | 3 | |
| Amyotrophic lateral sclerosis 20 | 615426 | Autosomal dominant | 3 |
In eukaryotic cells, nascent RNA polymerase II transcripts are associated in the nucleus with specific proteins to form ribonucleoprotein complexes called HNRP or 40S. Protein moiety of the 40S particle has 6 major components called core proteins, A1/A2, B1/B2, and C1/C2, plus a number of other proteins. Buvoli et al. (1988) isolated and sequenced the cDNA for human HNRPA1.
Biamonti et al. (1989) isolated an active HNRNPA1 gene. The gene contains 10 exons and spans 4.6 kb.
By nonisotopic in situ hybridization using a phage genomic clone that contained the active HNRNPA1 gene as well as 13.5-kb flanking sequences, Saccone et al. (1992) mapped the gene to chromosome 12q13.1. To suppress hybridization to pseudogene sequences, unlabeled HNRNPA1 cDNA was added in excess over the probe to the hybridization mixture.
Michael et al. (1995) reported that HNRPA1 shuttles continuously between the nucleus and cytoplasm and contains a 38-amino acid domain, termed M9, that acts as both a nuclear localization and nuclear export signal. They suggested that HNRPA1 and other shuttling hnRNPs function as carriers for RNA during export to the cytoplasm.
Pollard et al. (2000) sought to determine if the nuclear concentrations of the trans-acting splicing regulators SF2/ASF (600812) and HNRNPA1 and its splice variant, HNRNPA1B, are fundamental in regulating the expression of specific protein isoforms derived from alternative splicing of single pre-mRNA transcripts. SF2/ASF and HNRNPA1/A1B expression was determined in paired upper (corpus) and lower segment myometrial samples taken from individual women at term or during spontaneous labor and compared with nonpregnant control samples using specific monoclonal antibodies. SF2/ASF levels were substantially increased in the lower uterine region, and this was associated with a parallel decrease in levels of HNRNPA1/A1B during gestation. Conversely, the opposite pattern was observed within the upper uterine region during pregnancy, where HNRNPA1/A1B was significantly upregulated and SF2/ASF levels were much lower than those found in the lower uterine segment. The authors concluded that differential expression of HNRNPA1/A1B and SF2/ASF in the upper and lower uterine segments may have a primary role in defining the formation of specific myometrial protein species associated with the known contractile and relaxatory properties of these regions before and during parturition.
Kashima et al. (2007) identified a high-affinity HNRNPA1-binding site near exon 7 of the SMN2 gene (601627) and showed that HNRNPA1 promoted skipping of this exon. Depletion of HNRNPA1 and HNRNPA2 (600124) in HeLa cells restored exon 7 inclusion. Kashima et al. (2007) showed that disease-related exon-skipping mutations in BRCA1 (113705) and FBN1 (134797) introduced identical high-affinity HNRNPA1-binding sites. HNRNPA1 and HNRNPA2 depletion had no effect on splicing of mutant BRCA1, but it partially rescued splicing in FBN1. Kashima et al. (2007) concluded that HNRNPA1 functions as a splice site repressor.
Using coimmunoprecipitation analysis, Kim et al. (2007) found that the hepatitis C virus (HCV; see 609532) NS5b RNA polymerase interacted with HNRPA1. HNRPA1 also interacted with another NS5b-binding protein, SEPT6 (300683), suggesting the existence of a trimolecular complex. Knockdown of either HNRPA1 or SEPT6 inhibited HCV replication.
David et al. (2010) showed that 3 heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, polypyrimidine tract-binding protein (PTB, also known as hnRNPI; 600693), hnRNPA1, and hnRNPA2 (600124), bind repressively to sequences flanking exon 9 of the PKM2 gene (179050), resulting in exon 10 inclusion and the expression of the PKM2 (embryonic) isoform of muscle pyruvate kinase. David et al. (2010) also demonstrated that the oncogenic transcription factor c-MYC (190080) upregulates transcription of PTB, hnRNPA1, and hnRNPA2, ensuring a high PKM2/PKM1 ratio. Establishing a relevance to cancer, David et al. (2010) showed that human gliomas (137800) overexpress c-Myc, PTB, hnRNPA1, and hnRNPA2 in a manner that correlates with PKM2 expression. David et al. (2010) concluded that their results defined a pathway that regulates an alternative splicing event required for tumor cell proliferation.
Maintenance of telomeres requires both DNA replication and telomere capping by shelterin. These 2 processes use 2 single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA; see 179835) and protection of telomeres-1 (POT1; 606478). POT1 ablation leads to activation of the ataxia-telangiectasia and Rad3-related checkpoint kinase (ATR; 601215) at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, Flynn et al. (2011) found that purified POT1 and its functional partner TPP1 (609377) are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, they identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, Flynn et al. (2011) showed that hnRNPA1 recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the reaccumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Flynn et al. (2011) concluded that hnRNPA1, TERRA, and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.
Kim et al. (2013) reported that HNRNPA1 has a C-terminal glycine-rich domain that is essential for activity and mediates interaction with TDP43 (605078). This low-complexity domain is predicted to be intrinsically unfolded and has an amino acid composition similar to that of yeast prion domains. Approximately 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a similar distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. Kim et al. (2013) showed that HNRNPA1 has an intrinsic tendency to assemble into self-seeding fibrils.
By yeast 2-hybrid screening of a human brain cDNA library, Gilpin et al. (2015) found that the glycine-rich C-terminal ends of HNRNPA1, HNRNPA3 (605372), and HNRNPU (602869) interacted with the central domain of human UBQLN2 (300264). Protein interaction and coimmunoprecipitation assays confirmed binding between UBQLN2 and HNRNPA1 and HNRNPU. Knockdown of mouse Ubqln2 in NSC-34 motor neurons destabilized Hnrnpa1, increasing its turnover. All 5 ALS15 (300857)-associated mutations within a Pxx repeat in the central domain of UBQLN2 (300264.0001-300264.0005) reduced its interaction with HNRNPA1. Similarly, an IBMPFD3 (615424)-associated mutation in HNRNPA1 (D262V; 164017.0001) reduced its interaction with UBQLN2.
Buvoli et al. (1988) demonstrated by Southern analysis that HNRPA1-specific sequences are present in the human genome as a multigene family of about 30 members, most of them corresponding to pseudogenes of the processed type.
New World primates show relative target organ resistance to adrenal, gonadal, and vitamin D sterol/steroid hormones. This occurs in the absence of abnormal expression of cognate nuclear receptors. Rather, these animals have elevated levels of heterogeneous nuclear ribonucleoproteins (hnRNPs) that act as hormone response element-binding proteins and attenuate target gene transactivation. Chen et al. (2003) presented evidence for a similar mechanism in humans through study of a patient with resistance to the active form of vitamin D who presented with normal vitamin D receptor (VDR; 601769) expression. The patient presented with skeletal abnormalities and biochemical features classically associated with vitamin D-resistant rickets (277440). These included hypocalcemia, raised serum alkaline phosphatase, and raised circulating levels of 1,25-dihydroxyvitamin D3. Initial cotransfection studies showed that the cells of the patient suppressed basal and hormone-induced transactivation by wildtype VDR. Electrophoretic mobility-shift assays and Western/Southwestern blot analyses indicated that this suppressive effect was due to overexpression of a nuclear protein that specifically interacted with a DNA response element known to bind retinoid X receptor (see 180247)-VDR heterodimers. Antibody blocking in electrophoretic mobility-shift assays indicated that this dominant-negative-acting protein was in the hnRNPA family of nucleic acid-binding proteins. Further studies showed that several members of this family, most notably HNRNPA1, were able to suppress basal and 1,25-dihydroxyvitamin D3-induced luciferase activity. Therefore, Chen et al. (2003) proposed that vitamin D resistance in the patient was similar to that described in New World primates, in which abnormal expression of a hormone response element-binding protein can cause target cell resistance to vitamin D. That this protein is a member of the hnRNP family capable of interacting with double-stranded DNA highlights a potentially important new component of the complex machinery required for steroid hormone signal transduction.
Inclusion Body Myopathy and Alzheimer Disease
Kim et al. (2013) identified missense mutations in the HNRNPA1 gene in a family (family 2, originally described by Kottlors et al. (2010)) with an autosomal dominant multisystem proteinopathy (IBMPFD3; 615424). Different changes in the same domain resulted in autosomal dominant familial amyotrophic lateral sclerosis (ALS20; 615426).
By sequencing coding exons of the HNRNPA1 gene, Le Ber et al. (2014) failed to identify pathogenic mutations in a cohort of 17 unrelated French patients with sporadic or familial occurrence of multiple system proteinopathy manifest as frontotemporal lobar degeneration (FTLD) and/or amyotrophic lateral sclerosis (ALS) that segregated with Paget disease of bone (PDB), and/or inclusion body myositis (IBM). No mutations were found in 60 probands with FTLD or FTLD/ALS. By sequencing the prion-like domain of the HNRNPA1 gene, Seelen et al. (2014) also failed to identify any nonsynonymous mutations in 135 patients with familial ALS, 1,084 patients with sporadic ALS, 68 patients with familial FTLD, 74 patients with sporadic FTLD, and 31 patients with sporadic IBM. All patients were from the Netherlands. The findings of both studies suggested that mutations in HNRNPA1 are a very rare cause of this spectrum of diseases.
Distal Myopathy 3
In affected members of a large multigenerational Finnish family with distal myopathy-3 (MPD3; 610099) originally reported by Mahjneh et al. (2003), Hackman et al. (2021) identified a heterozygous 160-bp deletion affecting exon 10 of the HNRNPA1 gene, which encodes part of the PrLD domain (164017.0004). The deletion, which was found by a combination of linkage analysis, genome sequencing, and copy number variation analysis, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not present in the gnomAD database. Western blot analysis of skeletal muscle biopsy of 1 patient showed about 50% reduced expression of both HNRNPA1 isoforms. Muscle biopsies also showed small SQSTM1 (601530)- and larger TDP43 (605078)-labeled inclusions. Some biopsies showed increased HNRNPA1 sarcoplasmic labeling; 1 fiber in 1 biopsy showed moderate HNRNPA1 accumulation, but the authors noted that there was no strong focal cytoplasmic accumulation.
Associations Pending Confirmation
Expression of an alternatively spliced HMGCR transcript lacking exon 13 has been implicated in the variation of LDL cholesterol. Yu et al. (2014) sought to identify molecules that regulate HMGCR (142910) alternative splicing. They chose to follow HNRNPA1, because rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Yu et al. (2014) not only demonstrated that rs3846662 modulates HNRNPA1 binding, but also that sterol depletion of human hepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1 increased the ratio of HMGCR13(-) to total HMGCR transcripts by both directly increasing exon 13 skipping in an allele-related manner and specifically stabilizing the HMGCR13(-) transcript. Importantly, HNRNPA1 overexpression also diminished HMGCR enzyme activity, enhanced LDL-cholesterol uptake, and increased cellular apolipoprotein B (APOB; 107730). A SNP associated with HNRNPA1 exon 8 alternative splicing, rs1920045, was also associated with smaller statin-induced reduction in total cholesterol in 2 independent clinical trials. Yu et al. (2014) concluded that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.
In a family (family 2) with autosomal dominant inclusion body myopathy and Paget disease of the bone (IBMPFD3; 615424) originally described by Kottlors et al. (2010), Kim et al. (2013) identified an A-to-T transversion at nucleotide 941 in the long isoform of HNRNPA1 (785 in the short isoform) resulting in an asp314-to-val (D314V) (ASP262VAL, D262V in the short isoform). This mutation was not identified in the NHLBI Exome Sequencing Project and changed an aspartic acid conserved through Drosophila that is centered in a motif, the prion-like domain (PrLD), that is conserved in multiple human paralogs of the human HNRNPA/B family. The mutation was predicted to enhance prion-like behavior.
Gilpin et al. (2015) demonstrated that the D262V mutation in HNRNPA1 reduced its interaction with UBQLN2 (300264).
In a family segregating autosomal dominant ALS (ALS20; 615426), Kim et al. (2013) identified a heterozygous G-to-A transition at nucleotide 940 of the long isoform of HNRNPA1 (784 of the short isoform) that resulted in an aspartic acid-to-asparagine substitution at codon 314 (D314N; ASP262ASN, D262N in the short isoform). This mutation replaced the same highly conserved aspartic acid that was substituted in patients with IBMPFD3 (see 164017.0001). This mutation was not identified in the NHLBI Exome Sequencing Project.
In an individual with sporadic classic late-onset amyotrophic lateral sclerosis (ALS20; 615426), Kim et al. (2013) detected heterozygosity for an A-to-G transition at nucleotide 956 of the long isoform of HNRNPA1 (800 of the short isoform) that resulted in an asparagine-to-serine substitution at codon 319 (N319S; ASN267SER, N267S in the short isoform). This variant is centered in the core PrLD of HNRNPA1 and introduces a potent steric zipper that accelerates the formation of pathogenic fibrillization.
In affected members of a large multigenerational Finnish family with distal myopathy-3 (MPD3; 610099) originally reported by Mahjneh et al. (2003), Hackman et al. (2021) identified a heterozygous 160-bp deletion (chr12.54,677,979-54,678,138, NM_031157.4) affecting exon 10 of the HNRNPA1 gene, which encodes part of the PrLD domain. The deletion, which was found by a combination of linkage analysis, genome sequencing, and copy number variation analysis, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not present in the gnomAD database. A muscle sample from 1 of the patients showed an abnormal HNRNPA1 transcript that lacked exon 10. The observed splicing defect was predicted to result in a frameshift and premature termination (Gly356AsnfsTer4). The mutation was also predicted to encode a minor abnormal transcript leading to a longer C-terminal tail encoded by 3-prime UTR exons. Western blot analysis of skeletal muscle biopsy of 1 patient showed about 50% reduced expression of both HNRNPA1 isoforms. Muscle biopsies also showed small SQSTM1 (601530)- and larger TDP43 (605078)-labeled inclusions. Some biopsies showed increased HNRNPA1 sarcoplasmic labeling; 1 fiber in 1 biopsy showed moderate HNRNPA1 accumulation, but the authors noted that there was no strong focal cytoplasmic accumulation.
Biamonti, G., Buvoli, M., Bassi, M. T., Morandi, C., Cobianchi, F., Riva, S. Isolation of an active gene encoding human hnRNP protein A1: evidence for alternative splicing. J. Molec. Biol. 207: 491-503, 1989. [PubMed: 2760922] [Full Text: https://doi.org/10.1016/0022-2836(89)90459-2]
Buvoli, M., Biamonti, G., Tsoulfas, P., Bassi, M. T., Ghetti, A., Riva, S., Morandi, C. cDNA cloning of human hnRNP protein A1 reveals the existence of multiple mRNA isoforms. Nucleic Acids Res. 16: 3751-3770, 1988. [PubMed: 2836799] [Full Text: https://doi.org/10.1093/nar/16.9.3751]
Chen, H., Hewison, M., Hu, B., Adams, J. S. Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc. Nat. Acad. Sci. 100: 6109-6114, 2003. [PubMed: 12716975] [Full Text: https://doi.org/10.1073/pnas.1031395100]
David, C. J., Chen, M., Assanah, M., Canoll, P., Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: 364-368, 2010. [PubMed: 20010808] [Full Text: https://doi.org/10.1038/nature08697]
Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 471: 532-536, 2011. [PubMed: 21399625] [Full Text: https://doi.org/10.1038/nature09772]
Gilpin, K. M., Chang, L., Monteiro, M. J. ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1. Hum. Molec. Genet. 24: 2565-2577, 2015. [PubMed: 25616961] [Full Text: https://doi.org/10.1093/hmg/ddv020]
Hackman, P., Rusanen, S. M., Johari, M., Vihola, A., Jonson, P. H., Sarparanta, J., Donner, K., Lahermo, P., Koivunen, S., Luque, H., Soininen, M., Mahjneh, I., Auranen, M., Arumilli, M., Savarese, M., Udd, B. Dominant distal myopathy 3 (MPD3) caused by a deletion in the HNRNPA1 gene. Neurol. Genet. 7: e632, 2021. [PubMed: 34722876] [Full Text: https://doi.org/10.1212/NXG.0000000000000632]
Kashima, T., Rao, N., David, C. J., Manley, J. L. hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum. Molec. Genet. 16: 3149-3159, 2007. [PubMed: 17884807] [Full Text: https://doi.org/10.1093/hmg/ddm276]
Kim, C. S., Seol, S. K., Song, O.-K., Park, J. H., Jang, S. K. An RNA-binding protein, hnRNP A1, and a scaffold protein, septin 6, facilitate hepatitis C virus replication. J. Virol. 81: 3852-3865, 2007. [PubMed: 17229681] [Full Text: https://doi.org/10.1128/JVI.01311-06]
Kim, H. J., Kim, N. C., Wang, Y.-D., Scarborough, E. A., Moore, J., Diaz, Z., MacLea, K. S., Freibaum, B., Li, S., Molliex, A., and 25 others. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495: 467-473, 2013. [PubMed: 23455423] [Full Text: https://doi.org/10.1038/nature11922]
Kottlors, M., Moske-Eick, O., Huebner, A., Krause, S., Mueller, K., Kress, W., Schwarzwald, R., Bornemann, A., Haug, V., Heitzer, M., Kirschner, J. Late-onset autosomal dominant limb girdle muscular dystrophy and Paget's disease of bone unlinked to the VCP gene locus. J. Neurol. Sci. 291: 79-85, 2010. [PubMed: 20116073] [Full Text: https://doi.org/10.1016/j.jns.2009.12.008]
Le Ber, I., Van Bortel, I., Nicolas, G., Bouya-Ahmed, K., Camuzat, A., Wallon, D., De Septenville, A., Latouche, M., Lattante, S., Kabashi, E., Jornea, L., Hannequin, D., Brice, A., the French research Network on FTLD/FTLD-ALS. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with 'multisystem proteinopathy' and frontotemporal lobar degeneration phenotypes. Neurobiol. Aging 35: 934e5, 2014. Note: Electronic Article.
Mahjneh, I., Haravuori, H., Paetau, A., Anderson, L. V. B., Saarinen, A., Udd, B., Somer, H. A distinct phenotype of distal myopathy in a large Finnish family. Neurology 61: 87-92, 2003. [PubMed: 12847162] [Full Text: https://doi.org/10.1212/01.wnl.0000073618.91577.e8]
Michael, W. M., Choi, M., Dreyfuss, G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 83: 415-422, 1995. [PubMed: 8521471] [Full Text: https://doi.org/10.1016/0092-8674(95)90119-1]
Pollard, A. J., Sparey, C., Robson, S. C., Krainer, A. R., Europe-Finner, G. N. Spatio-temporal expression of the trans-acting splicing factors SF2/ASF and heterogeneous ribonuclear proteins A1/A1B in the myometrium of the pregnant human uterus: a molecular mechanism for regulating regional protein isoform expression in vivo. J. Clin. Endocr. Metab. 85: 1928-1936, 2000. [PubMed: 10843177] [Full Text: https://doi.org/10.1210/jcem.85.5.6537]
Saccone, S., Biamonti, G., Maugeri, S., Bassi, M. T., Bunone, G., Riva, S., Della Valle, G. Assignment of the human heterogeneous nuclear ribonucleoprotein A1 gene (HNRPA1) to chromosome 12q13.1 by cDNA competitive in situ hybridization. Genomics 12: 171-174, 1992. [PubMed: 1733858] [Full Text: https://doi.org/10.1016/0888-7543(92)90424-q]
Seelen, M., Visser, A. E., Overste, D. J., Kim, H. J., Palud, A., Wong, T. H., van Swieten, J. C., Scheltens, P., Voermans, N. C., Baas, F., de Jong, J. M. B. V., van der Kooi, A. J., de Visser, M., Veldink, J. H., Taylor, J. P., Van Es, M. A., van den Berg, L. H. No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Neurobiol. Aging 35: 1956e9, 2014. Note: Electronic Article.
Yu, C.-Y., Theusch, E., Lo, K., Mangravite, L. M., Naidoo, D., Kutilova, M., Medina, M. W. HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism. Hum. Molec. Genet. 23: 319-332, 2014. [PubMed: 24001602] [Full Text: https://doi.org/10.1093/hmg/ddt422]