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HGNC Approved Gene Symbol: HNRNPC
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:21,209,147-21,269,442 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Intellectual developmental disorder, autosomal dominant 74 | 620688 | Autosomal dominant | 3 |
The primary nuclear transcripts of RNA polymerase II, some of which are precursors to cytoplasmic mRNA (pre-mRNA), are collectively referred to as heterogeneous nuclear RNAs (hnRNAs). At least 20 of these proteins, designated A1 (34 kD) through U (120 kD), are present in abundance. In the nucleus they are found in association with a specific set of proteins to form ribonucleoprotein (hnRNP) particles. In vertebrates, the C proteins, C1 and C2, are major constituents of these particles. The 2 are antigenically closely related phosphoproteins, which bind tightly to RNA in vitro (Nakagawa et al., 1986).
Nakagawa et al. (1986) cloned cDNA for the hnRNA C proteins. Genomic blot analysis showed homologous DNA sequences across eukaryotes from human to yeast, indicating that the hnRNA C proteins are members of a conserved gene family. Burd et al. (1989) reported the complete primary structure of the hnRNP proteins A2, B1, and C2; A1, C1, and L had previously been sequenced. They suggested that the C1 and C2 proteins are produced by alternative splicing of a single gene transcript. Merrill et al. (1989) found that C1 and C2 differ by the presence of a 13-amino acid insert in C2, after either glycine-106 or serine-107 of C1. The additional 13 amino acids account for the molecular mass difference of C2 on SDS polyacrylamide gel electrophoresis. Otherwise C1 and C2 are identical; furthermore, the 3-prime and 5-prime untranslated portions of the 2 mRNAs are identical (Swanson et al., 1987).
Stumpf (2023) mapped the HNRNPC gene to chromosome 14q11.2 based on an alignment of the HNRNPC sequence (GenBank BC108658) with the genomic sequence (GRCh38).
Locus control regions (LCRs) are regulatory DNA sequences located many kilobases away from their cognate promoters. Mahajan et al. (2005) found that an LCR-associated remodeling complex (LARC) purified from a human erythroleukemia cell line exists as a single homogeneous complex of hnRNP C1 and C2, the chromatin remodeling SWI/SNF complex (see 600014), and the nucleosome remodeling and deacetylating (NURD; see 603526)/MECP1 (156535) complex.
Chen et al. (2006) purified the nuclear response element-binding protein (REBiP) identified by Chen et al. (2003) in a patient with vitamin D-dependent rickets type 2B (VDDR2B; 600785) and found a tryptic fragment bearing 100% sequence identity with the human hnRNP C1 and C2 proteins. Tryptic peptide sequencing followed by Western blot analysis confirmed that cells from the VDDR2B patient overexpressed a pair of anti-hnRNP C1/C2-reactive proteins of 39-40 kD, compatible with the hnRNPC1 and the slightly larger hnRNPC2. When overexpressed in vitamin D-responsive cells, cDNAs for both C1 and C2 inhibited VDR (vitamin D receptor; 601769)-VDRE (vitamin D response element)-directed transactivation by 23% and 42%, respectively (p less than 0.005 for both). In contrast, transient expression of an hnRNP C1/C2 small interfering RNA (siRNA) increased VDR transactivation by 39% (p less than 0.005). Chromatin immunoprecipitation studies revealed the presence of REBiP in vitamin D-responsive human cells and indicated that the normal pattern of 1,25-dihydroxy vitamin D-initiated cyclical movement of the VDR on and off the VDRE is legislated by competitive, reciprocal occupancy of the VDRE by hnRNP C1/C2. The temporal and reciprocal pattern of VDR and hnRNP C1/C2 interaction with the VDRE was lost in VDDR2B cells overexpressing the hnRNP C1/C2 REBiP. Chen et al. (2006) stated that their work provided further evidence that hnRNPs are able to influence gene transcription itself by acting as binding proteins for hormone response elements and suggested that hnRNP C1/C2 may be a key determinant of the temporal patterns of VDRE occupancy.
In human cells, Liu et al. (2015) demonstrated that m6A (see 610640) controls the RNA structure-dependent accessibility of RNA binding motifs to affect RNA-protein interactions for biologic regulation; they termed this mechanism 'the m6A switch.' Liu et al. (2015) found that m6A alters the local structure in mRNA and long noncoding RNA to facilitate binding of HNRNPC. Combining photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m6A immunoprecipitation approaches enabled Liu et al. (2015) to identify 39,060 m6A switches among HNRNPC binding sites. Global m6A reduction decreased HNRNPC binding at 2,798 high-confidence m6A switches. Liu et al. (2015) determined that these m6A switch-regulated HNRNPC binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A switches on gene expression and RNA maturation. Liu et al. (2015) concluded that their results illustrated how RNA binding proteins gain regulated access to their RNA binding motifs through m6A-dependent RNA structural remodeling.
Niggl et al. (2023) reported 13 unrelated patients with autosomal dominant intellectual developmental disorder-74 (MRD74; 620688) associated with heterozygous variants, mostly de novo, in the HNRNPC gene ascertained through the GeneMatcher program. One individual (Ind10) carried a larger deletion that included the HNRNPC gene and extended into adjacent genes. Five individuals (Ind1-Ind5) carried a recurrent de novo heterozygous 9-residue in-frame deletion (HNRNPC(del); 164020.0001) that affected the C terminus, and the transcript escaped nonsense-mediated mRNA decay. The 7 other individuals had heterozygous frameshift (4 patients, see, e.g., 164020.0002) or missense (3 patients) variants. Of note, some of these individuals carried additional variants of uncertain significance in other genes, parental samples were not available for 2 patients, and 2 patients inherited the variants from their unaffected mothers who were mosaic. Detailed in vitro cellular studies showed that HNRNPC(del) did not cause a loss-of-function, dominant-negative, or gain-of-function effect, but likely results in haploinsufficiency. In silico computational metaanalysis of published data suggested that loss of HNRNPC results in alternative splicing of multiple target genes, including a subset of genes associated with intellectual disability. RNA-seq analysis of fibroblasts derived from Ind8, who carried a de novo heterozygous frameshift variant (164020.0002), showed some evidence of alternative splicing that was similar to that identified in the metaanalysis (about a 52% overlap of alternative exon or ALU sequences). However, iPSCs from Ind1 with the HNRNPC(del) variant did not show splice site alterations in any of the genes identified in the metaanalysis, which the authors attributed to the differences in cell type. ShRNA-mediated knockdown of the Hnrnpc gene in murine primary neuronal cultures resulted in decreased neurite length and arborization compared to controls. Overexpression of both wildtype HNRNPC and HNRNPC(del) caused reduced neuronal soma area, neurite length, and dendrite arborization; moreover, the dendrites in cells overexpressing the wildtype and variant genes deteriorated 5 days posttransfection, while those in control cells developed normally. In utero electroporation of mouse embryos to express HNRNPC shRNAs, HNRNPC isoform 1 (wildtype), and HNRNPC(del) in immature neurons of the subventricular zone all resulted in delayed neuronal migration during early cortical development. The findings indicated that the HNRNPC(del) variant behaves like the wildtype protein and that its pathogenic effect is caused by the reduction of HNRNPC levels. The authors concluded that correct dosage of HNRNPC is critical for normal neuronal development and function.
In 5 unrelated patients (Ind1-Ind5) with autosomal dominant intellectual developmental disorder-74 (MRD74; 620688), Niggl et al. (2023) identified a recurrent de novo heterozygous 27-bp in-frame deletion in the last exon of the HNRNPC gene. The deletion in isoform 1, which lacks the C2 domain but is more abundant, is notated c.850_876del (c.850_876del, NM_004500.4) (Arg284_Asp292del), and the deletion in isoform 2 is notated c.889_915del (c.889_915del, NM_031314.3) (Arg297_Asp305del). The deletion resulted in loss of the C-terminal end of the protein, and the transcript escaped nonsense-mediated mRNA decay. The authors referred to this mutation as HNRNPC(del). The variant, which was found by exome sequencing, was present in 1 individual in the gnomAD database (frequency of 6.57 x 10(-6)), who the authors suggested was mosaic or only mildly affected. Induced pluripotent stem cells (iPSCs) derived from Ind1 and HEK293 cells transfected with this variant showed the presence of a truncated protein at decreased levels, resulting in significantly reduced levels of total HNRNPC to 45% of controls. Detailed in vitro cellular studies showed that HNRNPC(del) localized normally to the nucleus, was able to form HNRNPC oligomers, and did not cause abnormal mRNA accumulation. Overall, these findings suggested that the HNRNPC(del) variant does not cause a loss-of-function, dominant-negative, or gain-of-function effect, but likely results in haploinsufficiency. ShRNA-mediated knockdown of the Hnrnpc gene in murine primary neuronal cultures resulted in decreased neurite length and arborization compared to controls. Overexpression of both wildtype HNRNPC and HNRNPC(del) caused reduced neuronal soma area, neurite length, and dendrite arborization; moreover, the dendrites in cells overexpressing the wildtype and variant genes deteriorated 5 days posttransfection, while those in control cells developed normally. In utero electroporation of mouse embryos to express HNRNPC shRNAs, HNRNPC isoform 1 (wildtype), and HNRNPC(del) in immature neurons of the subventricular zone all resulted in delayed neuronal migration during early cortical development. The findings indicated that the HNRNPC(del) variant behaves like the wildtype protein and that its pathogenic effect is caused by the reduction of HNRNPC levels. The authors concluded that correct dosage of HNRNPC is critical for normal neuronal development and function.
In a 7-year-old boy (Ind8) with autosomal dominant intellectual developmental disorder-74 (MRD74; 620688), Niggl et al. (2023) identified a de novo heterozygous 1-bp deletion (c.754del, NM_004500.4) in the last exon of the HNRNPC gene, resulting in a frameshift and premature termination (Asp252ThrfsTer18 in isoform 1). The mutation, which was found by whole-genome sequencing, was predicted to escape nonsense-mediated mRNA decay. In silico computational metaanalysis of published data suggested that loss of HNRNPC results in alternative splicing of multiple target genes, including a subset of genes associated with intellectual disability. RNA-seq analysis of fibroblasts derived from Ind8 showed some evidence of alternative splicing that was similar to that identified in the metaanalysis (about a 52% overlap of alternative exon or ALU sequences). The authors concluded that haploinsufficiency of HNRNPC is the pathogenic mechanism responsible for abnormal neurodevelopment.
Burd, C. G., Swanson, M. S., Gorlach, M., Dreyfuss, G. Primary structures of the heterogeneous nuclear ribonucleoprotein A2, B1, and C2 proteins: a diversity of RNA binding proteins is generated by small peptide inserts. Proc. Nat. Acad. Sci. 86: 9788-9792, 1989. [PubMed: 2557628] [Full Text: https://doi.org/10.1073/pnas.86.24.9788]
Chen, H., Hewison, M., Adams, J. S. Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein. J. Biol. Chem. 281: 39114-39120, 2006. [PubMed: 17071612] [Full Text: https://doi.org/10.1074/jbc.M608006200]
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]
Liu, N., Dai, Q., Zheng, G., He, C., Parisien, M., Pan, T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518: 560-564, 2015. [PubMed: 25719671] [Full Text: https://doi.org/10.1038/nature14234]
Mahajan, M. C., Narlikar, G. J., Boyapaty, G., Kingston, R. E., Weissman, S. M. Heterogeneous nuclear ribonucleoprotein C1/C2, MeCP1, and SWI/SNF form a chromatin remodeling complex at the beta-globin locus control region. Proc. Nat. Acad. Sci. 102: 15012-15017, 2005. [PubMed: 16217013] [Full Text: https://doi.org/10.1073/pnas.0507596102]
Merrill, B. M., Barnett, S. F., LeStourgeon, W. M., Williams, K. R. Primary structure differences between proteins C1 and C2 of HeLa 40S nuclear ribonucleoprotein particles. Nucleic Acids Res. 17: 8441-8449, 1989. [PubMed: 2587210] [Full Text: https://doi.org/10.1093/nar/17.21.8441]
Nakagawa, T. Y., Swanson, M. S., Wold, B. J., Dreyfuss, G. Molecular cloning of cDNA for the nuclear ribonucleoprotein particle C proteins: a conserved gene family. Proc. Nat. Acad. Sci. 83: 2007-2011, 1986. [PubMed: 3457372] [Full Text: https://doi.org/10.1073/pnas.83.7.2007]
Niggl, E., Bouman, A., Briere, L. C., Hoogenboezem, R. M., Wallaard, I., Park, J., Admard, J., Wilke, M., Harris-Mostert, E. D. R. O., Elgersma, M., Bain, J., Balasubramanian, M., and 28 others. HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder. Am. J. Hum. Genet. 110: 1414-1435, 2023. [PubMed: 37541189] [Full Text: https://doi.org/10.1016/j.ajhg.2023.07.005]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/25/2023.
Swanson, M. S., Nakagawa, T. Y., LeVan, K., Dreyfuss, G. Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins. Molec. Cell. Biol. 7: 1731-1739, 1987. [PubMed: 3110598] [Full Text: https://doi.org/10.1128/mcb.7.5.1731-1739.1987]