Alternative titles; symbols
HGNC Approved Gene Symbol: C1QBP
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:5,432,777-5,439,155 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Combined oxidative phosphorylation deficiency 33 | 617713 | Autosomal recessive | 3 |
The C1QBP gene encodes an evolutionarily conserved and ubiquitously expressed multifunctional protein. It has been reported to be a predominantly mitochondrial matrix protein involved in inflammation and infection processes, mitochondrial ribosome biogenesis, regulation of apoptosis and nuclear transcription, and pre-mRNA splicing (summary by Feichtinger et al., 2017).
Krainer et al. (1991) described a protein in HeLa cells that was copurified with the pre-mRNA splicing factor SF2 (600812). They cloned a cDNA that encoded the protein, which contains arginine-serine dipeptide (RS) domains similar to those found in the U1 SnRNP 70-kD polypeptide. The cDNA sequence was identical to one described by Honore et al. (1993), who also cloned an additional 5-prime end sequence. The gene encodes a 282-amino acid proprotein and is posttranslationally processed by removal of the first 73 residues to a final 209-amino acid product.
Deb and Datta (1996) reported the cloning of a partial cDNA for a 34-kD hyaluronic acid-binding protein. That protein is present normally as a 68-kD homodimer. Antibodies raised against it were used for immunoscreening of an expression cDNA library of human skin fibroblasts. The cDNA sequence was identical to the splicing factor obtained by Krainer et al. (1991) and Honore et al. (1993). The predicted protein is highly acidic (estimated pI of 4.04) and contains a hyaluronic acid-binding domain as found in a protein called hyaladherin (107269). The protein contains a potential tyrosine sulfation site, 3 predicted N-linked glycosylation sites, and at least 1 potential phosphorylation site for kinases like ERK (see 176948), CDC2 (116940), and casein kinase II (115440). The recombinant protein, expressed in E. coli, was shown to bind hyaluronic acid-Sepharose.
The functions of C1q, the recognition subunit of the first component of the classical pathway of complement activation, are regulated by 2 distinct types of proteins that bind either the collagen or the globular domain. From a B-cell library, Ghebrehiwet et al. (1994) cloned the cDNA for the protein that binds the globular domain and established its primary structure. The protein, designated C1QBP, is identical to HABP1.
Feichtinger et al. (2017) found localization of the C1QBP gene to mitochondria in fibroblasts.
Zheng et al. (2003) noted that replication of human immunodeficiency virus-1 (HIV-1) is blocked in mouse cells at the levels of entry, transcription, and assembly, with the latter effect possibly resulting from excessive splicing of HIV-1 transcripts. They determined that transfection of human C1QBP, but not mouse C1qbp, which they called p32, blocked excessive splicing of viral genomic RNA. Mouse C1qbp has aspartic acid at position 35 of the mature processed protein, whereas human C1QBP has glycine at this position. Zheng et al. (2003) showed that the aspartic acid in mouse C1qbp is responsible for the posttranscriptional block to HIV replication.
Lamellipodia formation initiates directed cell migration by providing temporary focal adhesion sites for cells to move themselves toward a chemical signal. Using immunofluorescence microscopy and Western blot analysis, Kim et al. (2011) demonstrated that gC1QR was concentrated in lamellipodia together with CD44 (107269), monosialoganglioside, actin, and phosphorylated focal adhesion kinase (FAK, or PTK2; 600758) in human A549 lung carcinoma cells stimulated with insulin, IGF1 (147440), EGF (131530), or serum. A549 cells depleted of gC1QR showed decreased lamellipodia formation, FAK activation, and proliferation in response to growth factors. In grafted mice, A549 cells depleted of gC1QR had reduced tumorigenic and metastatic activity. Kim et al. (2011) concluded that cell surface gC1QR regulates lamellipodia formation and metastasis through receptor tyrosine kinase activation.
By fluorescence in situ hybridization (FISH), Majumdar and Datta (1998) mapped the human HABP1 gene to 17p13-p12. By the same method, Guo et al. (1997) mapped the C1QBP gene to 17p13.3 in a region conserved with mouse chromosome 11.
In 4 unrelated patients with variable manifestations of combined oxidative phosphorylation deficiency-33 (COXPD33; 617713), Feichtinger et al. (2017) identified homozygous or compound heterozygous mutations in the C1QBP gene (601269.0001-601269.0006). The mutations were found by whole-exome or targeted sequencing and confirmed by Sanger sequencing; the mutations segregated in all 3 families who were tested. Patient tissue showed highly variable decreases in multiple OXPHOS protein subunits and complex activities. Patient-derived skeletal muscle and/or fibroblasts showed decreased or even absent levels of the C1QBP protein, suggesting that the mutations result in protein instability in some tissues, but the results were inconsistent. The mouse variants of 2 mutations found in 1 patient (patient S2) (L275P; 601269.0003 and G247W; 601269.0004) were unable to complement the mitochondrial respiratory defects in fibroblasts derived from C1qbp-null mice, consistent with a loss-of-function effect.
Yagi et al. (2012) found the C1qbp-null mice showed midgestation lethality associated with a severe developmental defect of the embryo. Primary embryonic fibroblasts isolated from mutant embryos showed severe dysfunction of the mitochondrial respiratory chain due to impaired mitochondrial protein synthesis. The findings suggested that C1qbp is required for functional mitoribosome formation to synthesize proteins within mitochondria.
In a male infant (individual 1) of European descent with combined oxidative phosphorylation deficiency-33 (COXPD33; 617713), Feichtinger et al. (2017) identified compound heterozygous missense mutations in the C1QBP gene: a c.557G-C transversion (c.557G-C, NM_001212.3) in exon 4, resulting in a cys186-to-ser (C186S) substitution, and a c.612C-G transversion in exon 5, resulting in a phe204-to-leu (F204L; 601269.0002) substitution. The patient died at 18 days of age. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Screening of an in-house database of more than 10,000 whole-exome datasets of individuals with nonmitochondrial disease revealed no additional individual with biallelic rare variants in C1QBP. Neither variant was found in the 1000 Genomes Project database, but both were found at a low frequencies in the ExAC database. Functional studies of the variants were not performed.
For discussion of the c.612C-G transversion (c.612C-G, NM_001212.3) in the C1QBP gene, resulting in a phe204-to-leu (F204L) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-33 (COXPD33; 617713) by Feichtinger et al. (2017), see 601269.0001.
In a female infant (individual 2) of Japanese descent with combined oxidative phosphorylation deficiency-33 (COXPD33; 617713), Feichtinger et al. (2017) identified compound heterozygous missense mutations in the C1QBP gene: a c.824T-C transition (c.824T-C, NM_001212.3) in exon 6, resulting in a leu275-to-pro (L275P) substitution, and a c.739G-T transversion in exon 6, resulting in a gly247-to-trp (G247W; 601269.0004) substitution. This patient died at 4 days of age. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Screening of an in-house database of more than 10,000 whole-exome datasets of individuals with nonmitochondrial disease revealed no additional individual with biallelic rare variants in C1QBP. Neither variant was found in the 1000 Genomes Project or ExAC databases. The mouse equivalents of these mutations (G244W and L272P) were unable to complement the mitochondrial respiratory defects in fibroblasts derived from C1qbp-null mice, consistent with a loss-of-function effect. G244W showed normal expression levels, whereas L272P resulted in no detectable mutant protein, suggesting reduced protein expression or increased protein turnover.
For discussion of the c.739G-T transversion (c.739G-T, NM_001212.3) in the C1QBP gene, resulting in a gly247-to-trp (G247W) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-33 (COXPD33; 617713) by Feichtinger et al. (2017), see 601269.0003.
In a 22-year-old man (individual 3) with combined oxidative phosphorylation deficiency-33 (COXPD33; 617713), Feichtinger et al. (2017) identified a homozygous c.823C-T transition (c.823C-T, NM_001212.3) in exon 6 of the C1QBP gene, resulting in a leu275-to-phe (L275F) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Screening of an in-house database of more than 10,000 whole-exome datasets of individuals with nonmitochondrial disease revealed no additional individual with biallelic rare variants in C1QBP. The variant was not found in the 1000 Genomes Project or ExAC databases. (In the article by Feichtinger et al. (2017), this variant is given as L275P on page 529 but as L275F in Table 1.)
In a man of European descent (individual 4) with adult-onset combined oxidative phosphorylation deficiency-33 (COXPD33; 617713), Feichtinger et al. (2017) identified a homozygous 3-bp in-frame deletion (c.562_564delTAT, NM_001212.3) in exon 4 of the C1QBP gene, resulting in the deletion of a conserved residue (Tyr188del). The mutation was found by targeted sequencing of a mitochondrial gene panel and confirmed by Sanger sequencing. DNA from family members was not available. Screening of an in-house database of more than 10,000 whole-exome datasets of individuals with nonmitochondrial disease revealed no additional individual with biallelic rare variants in C1QBP. The variant was not found in the 1000 Genomes Project database, but was present at a low frequency in the ExAC database.
Deb, T. B., Datta, K. Molecular cloning of human fibroblast hyaluronic acid-binding protein confirms its identity with P-32, a protein co-purified with splicing factor SF2: hyaluronic acid-binding protein as P-32 protein, co-purified with splicing factor SF2. J. Biol. Chem. 271: 2206-2212, 1996. [PubMed: 8567680] [Full Text: https://doi.org/10.1074/jbc.271.4.2206]
Feichtinger, R. G., Olahova, M., Kishita, Y., Garone, C., Kremer, L. S., Yagi, M., Uchiumi, T., Jourdain, A. A., Thompson, K., D'Souza, A. R., Kopajtich, R., Alston, C. L., and 27 others. Biallelic C1QBP mutations cause severe neonatal-, childhood-, or later-onset cardiomyopathy associated with combined respiratory-chain deficiencies. Am. J. Hum. Genet. 101: 525-538, 2017. [PubMed: 28942965] [Full Text: https://doi.org/10.1016/j.ajhg.2017.08.015]
Ghebrehiwet, B., Lim, B.-L., Peerschke, E. I., Willis, A. C., Reid, K. B. Isolation, cDNA cloning, and overexpression of a 33-kDa cell surface glycoprotein that binds to the globular 'heads' of C1q. J. Exp. Med. 179: 1809-1821, 1994. [PubMed: 8195709] [Full Text: https://doi.org/10.1084/jem.179.6.1809]
Guo, N., Weremowicz, S., Lynch, N., Lim, B.-L., Schwaeble, W., Peerschke, E. I. B., Morton, C. C., Reid, K. B. M., Ghebrehiwet, B., Sastry, K. N. Assignment of C1QBP encoding the C1q globular domain binding protein (gC1q-R) to human chromosome 17 band p13.3 by in situ hybridization. Cytogenet. Cell Genet. 77: 283-284, 1997. [PubMed: 9284938] [Full Text: https://doi.org/10.1159/000134598]
Honore, B., Madsen, P., Rasmussen, H. H., Vandekerckhove, J., Celis, J. E., Leffers, H. Cloning and expression of a cDNA covering the complete coding region of the P32 subunit of human pre-mRNA splicing factor SF2. Gene 134: 283-287, 1993. [PubMed: 8262387] [Full Text: https://doi.org/10.1016/0378-1119(93)90108-f]
Kim, K.-B., Yi, J.-S., Nguyen, N., Lee, J.-H., Kwon, Y.-C., Ahn, B.-Y., Cho, H., Kim, Y. K., Yoo, H.-J., Lee, J.-S., Ko, Y.-G. Cell-surface receptor for complement component C1q (gC1qR) is a key regulator for lamellipodia formation and cancer metastasis. J. Biol. Chem. 286: 23093-23101, 2011. [PubMed: 21536672] [Full Text: https://doi.org/10.1074/jbc.M111.233304]
Krainer, A. R., Mayeda, A., Kozak, D., Binns, G. Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70K, and Drosophila splicing regulators. Cell 66: 383-394, 1991. [PubMed: 1830244] [Full Text: https://doi.org/10.1016/0092-8674(91)90627-b]
Majumdar, M., Datta, K. Assignment of cDNA encoding hyaluronic acid-binding protein 1 to human chromosome 17p12-p13. Genomics 51: 476-477, 1998. [PubMed: 9721222] [Full Text: https://doi.org/10.1006/geno.1998.5364]
Yagi, M., Uchiumi, T., Takazaki, S., Okuno, B., Nomura, M., Yoshida, S., Kanki, T., Kang, D. p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability. Nucleic Acids Res. 40: 9717-9737, 2012. [PubMed: 22904065] [Full Text: https://doi.org/10.1093/nar/gks774]
Zheng, Y.-H., Yu, H.-F., Peterlin, B. M. Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nature Cell Biol. 5: 611-618, 2003. Note: Erratum: Nature Cell Biol. 5: 839 only, 2003. [PubMed: 12833064] [Full Text: https://doi.org/10.1038/ncb1000]