Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: SERPINH1
SNOMEDCT: 312974005;
Cytogenetic location: 11q13.5 Genomic coordinates (GRCh38): 11:75,562,253-75,572,783 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.5 | {Preterm premature rupture of the membranes, susceptibility to} | 610504 | Multifactorial | 3 |
| Osteogenesis imperfecta, type X | 613848 | Autosomal recessive | 3 |
Collagen-binding proteins, or colligins, are glycoproteins that bind specifically to collagen type I (e.g., 120150, 120160), collagen type IV (e.g., 120130), and gelatin. Colligins are characterized by an amino acid structure that includes an N-terminal hydrophobic signal sequence and 2 putative N-linked oligosaccharide attachment sites (Clarke et al., 1991). Colligins also have a C-terminal RDEL sequence that acts as an endoplasmic reticulum (ER) retention sequence. Other features permit the colligin-binding protein of ER to be classified as a serpin (serine-arginine protease inhibitor).
Ikegawa et al. (1995) isolated and characterized a full-length human cDNA clone that encodes a 418-amino acid peptide highly homologous (97% identity) to the human colligin-1 gene (CBP1) reported by Clarke and Sanwal (1992). Nagai et al. (1999) later found that CBP1 is not transcribed and represents a pseudogene located on chromosome 9. Ikegawa et al. (1995) called the novel gene colligin-2 and identified a genomic clone that contained the entire coding sequence of the cDNA. The authors found that the colligin-2 gene is expressed ubiquitously among all normal human tissues except brain and circulating leukocytes.
Nagai et al. (1999) cloned CBP2 from a human skin fibroblast cDNA library using mouse Hsp47 cDNA as probe. By sequence analysis, they determined that CBP2 and Hsp47 are identical.
Ikegawa and Nakamura (1997) found that the CBP2 gene spans approximately 11 kb of genomic DNA and contains 5 exons.
By fluorescence in situ hybridization Ikegawa et al. (1995) determined that the CBP2 gene maps to chromosome 11q13.5.
Ikegawa and Nakamura (1997) noted that the promoter sequence of the human CBP2 gene shows significant homology to that of its murine counterpart, which contains several regulatory sequences including heat-shock and retinoic acid-responsive elements. The findings suggested that colligin may function as a collagen-specific molecular chaperone and play a role in the process of retinoic acid-induced differentiation.
Hattori et al. (1998) found that CBP2, synthesized by a chondrocytic cell line, is recognized as an antigen by sera from rheumatoid arthritis (RA; 180300) patients. They designated the protein RA-A47 due to its apparent molecular mass of 47 kD by SDS/PAGE. They also found that heat-shock treatment or exposure of cells to TGF-beta (see 190180) enhanced the expression of a 2-kb CBP2 transcript. Tasab et al. (2000) presented evidence that mammalian CBP2, which they called Hsp47, preferentially interacted with triple-helical procollagen molecules in vitro. The association of CBP2 with procollagen coincided with the formation of a collagen triple helix. Yasuda et al. (2002) found that, in mice, Kruppel-like factor Zf9 (602053) regulated the transcription of Cbp2 by binding the BS5-B promoter element in cooperation with Sp2 (601801) and/or Sp3 (601804).
In an individual with a severe deforming form of OI (OI10; 613848), Christiansen et al. (2010) identified a homozygous mutation in the SERPINH1 gene (600943.0002) that resulted in degradation of the endoplasmic reticulum resident HSP47 via proteasome. Type I procollagen accumulated in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen was protease sensitive. Christiansen et al. (2010) suggested that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and the helical structure is compromised. The normal 3-hydroxylation of the prolyl residue at position 986 of the triple helical domain of pro-alpha1(I) chains places the role of HSP47 downstream from the CRTAP/P3H1/CyPB complex that is involved in prolyl 3-hydroxylation.
By proteomic analysis, Thienel et al. (2023) identified Hsp47 as the most downregulated gene during hibernation of Swedish brown bears, as Hsp47 expression in platelets was 55-fold lower in hibernating bears compared with active bears. The authors noted that HSP47 is conserved across species. Mice with specific deletion of Hsp47 in the platelet compartment displayed drastically reduced thrombus frequency and sizes, with reduced thrombin binding to platelets and overall reduced biomarkers of thromboinflammation compared with controls. Analysis with human platelets revealed that HSP47 regulated thromboinflammation by facilitating thrombin binding to platelet surfaces as well as neutrophil activation through the TLR2 (603028)-MYD88 (602170) signaling axis. The results suggested a protective role of HSP47 downregulation against venous thromboembolism during chronic immobilization. HSP47 expression correlated with thrombogenicity in immobilized patients, and the interplay between platelets and neutrophils was one of the main causes of thrombogenic differences in acute and chronic immobilization. Moreover, platelet HSP47 expression was drastically decreased in healthy individuals after 27 days of bed rest and in pigs limited in mobility for 21 to 28 days.
Preterm Premature Rupture of the Membranes
In a search for genetic factors contributing to the higher prevalence of preterm premature rupture of the membranes (PPROM; 610504) in African American than in European American women, Wang et al. (2006) confirmed a higher frequency of a -656C-T SNP (600943.0001) in the promoter of the SERPINH1 gene in African and African American populations than in European Americans (7.4% versus 4.1%). In 2 case-control studies of African American neonates from pregnancies complicated by PPROM, the authors found a significant association between the -656T allele and PPROM. Wang et al. (2006) noted that SERPINH1 is located on chromosome 11q22.2 at approximately 27 Mb from MMP8 (120355), another gene that has been associated with PPROM, but stated that they found no evidence for linkage disequilibrium between the -656C-T SERPINH1 SNP and the previously studied MMP8 alleles.
Osteogenesis Imperfecta, Type X
Because the SERPINH1 gene encodes a collagen-binding protein that functions as a chaperone in the endoplasmic reticulum, Christiansen et al. (2010) screened for mutations in this gene in individuals with OI whose cells did not produce overmodified type I collagen. In 1 individual, born to clinically normal consanguineous Saudi Arabian parents, they identified a homozygous missense mutation (L78P; 600943.0002). The patient had a severe deforming form of OI, here designated OI type X (OI10; 613848). The authors stated that the disorder clinically fit into the OI type III Sillence classification.
In a 4-year-old girl with a moderately severe form of OI, Duran et al. (2015) identified homozygosity for a missense mutation in the SERPINH1 gene (M237T; 600943.0003) that segregated with disease in the family. In experiments using cultured patient dermal fibroblasts, the authors demonstrated that protein levels of both HSP47 and FKBP65 (FKBP10, 607063; see OI11, 610968) were reduced and mislocalized, and proximity ligation assays indicated that the proteins interact in subcellular compartments. Duran et al. (2015) suggested that the similarity in phenotype between OI10 and OI11 might be explained by the similar consequences on type I procollagen synthesis.
Nagai et al. (1999) found that Cbp2 knockout was lethal to embryonic mice.
Using a SNP-based homozygosity mapping strategy, Drogemuller et al. (2009) identified a homozygous mutation (c.977C-T) in the Serpinh1 gene as a candidate causative mutation for osteogenesis imperfecta in Dachshunds. The mutation resulted in the substitution of the highly conserved leu326 to pro (L326P) in an evolutionary conserved domain of Serpinh1. Homology modeling predicted that the L326P mutation affected the 3-dimensional structure of the protein.
In a study of ethnic/racial distribution and a -656C-T SNP in the promoter of the SERPINH1 gene, Wang et al. (2006) found that the -656T allele had a greater frequency in African and African American populations than in European Americans (12.4% vs 4.1%). The -656T allele displayed significantly reduced promoter activity compared to the wildtype -656C allele in amnion fibroblasts. Two independent case-control studies of African American neonates from pregnancies complicated by preterm premature rupture of the membranes (PPROM; 610504) revealed a significant association between the -656T allele and PPROM (p less than 0.0009 and 0.0076, respectively); combining the 2 studies (244 cases and 358 controls) resulted in a highly significant association between the -656T allele and PPROM (p less than 0.0000045). Wang et al. (2006) stated that this was the first example of an ancestry-informative marker associated with preterm birth in African Americans.
In a Saudi Arabian patient with osteogenesis imperfecta X (OI10; 613848), Christiansen et al. (2010) identified homozygosity for a 233T-C transition in the SERPINH1 gene, resulting in a leu78-to-pro (L78P) substitution. The parents were heterozygous for the mutation. The patient was the only affected member of the family. The mutation did not affect posttranslational modification of type I procollagen. It appeared to accelerate transit of type I procollagen from the ER to the Golgi but slightly slowed the overall transit time from inside the cell to the extracellular environment. The overall rate of type I procollagen production was, however, effectively normal, but the triple helical conformation of secreted type I collagen was altered so that secreted type I collagen was protease sensitive at one or more specific sites.
In a 4-year-old girl with a moderately severe form of OI (OI10; 613848), Duran et al. (2015) identified homozygosity for a c.710T-C transition in the SERPINH1 gene, resulting in a met237-to-thr (M237T) substitution at a highly conserved residue within the serine-type endopeptidase inhibitor domain. The unaffected third-cousin parents were heterozygous carriers of the mutation; DNA from an affected brother was not available. In experiments using cultured patient dermal fibroblasts, Duran et al. (2015) demonstrated that protein levels of both HSP47 and FKBP65 (FKBP10, 607063; see OI11, 610968) were reduced and mislocalized into vacuolar-like compartments. FKBP10-null cells did not show a reciprocal effect on HSP47 protein levels, but some HSP47 was mislocalized. Proximity ligation assay in control cells showed interaction of HSP47 and FKBP65 as single dots in the cytoplasm; in HSP47-mutant cells, the number of interactions was reduced and the interactions were clustered in a narrow area. Duran et al. (2015) suggested that HSP47 and FKBP65 interact or work in very close proximity, and that abnormalities in either protein result in abnormal trafficking, which drags a significant fraction of the complex into vesicles. In further experiments, they observed that type I procollagen maintained its normal localization in the ER and Golgi in HSP47-mutant or FKBP10-null cells, but was also found in the HSP47- and FKBP65-accumulating vesicles, suggesting that some type I procollagen molecules are not processed normally and could be recycled or removed along with the defective chaperones.
Christiansen, H. E., Schwarze, U., Pyott, S. M., AlSwaid, A., Al Balwi, M., Alrasheed, S., Pepin, M. G., Weis, M. A., Eyre, D. R., Byers, P. H. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am. J. Hum. Genet. 86: 389-398, 2010. [PubMed: 20188343] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.034]
Clarke, E. P., Cates, G. A., Ball, E. H., Sanwal, B. D. A collagen-binding protein in the endoplasmic reticulum of myoblasts exhibits relationship with serine protease inhibitors. J. Biol. Chem. 266: 17230-17235, 1991. [PubMed: 1654327]
Clarke, E. P., Sanwal, B. D. Cloning of a human collagen-binding protein, and its homology with rat gp46, chick hsp47 and mouse J6 proteins. Biochim. Biophys. Acta 1129: 246-248, 1992. [PubMed: 1309665] [Full Text: https://doi.org/10.1016/0167-4781(92)90498-o]
Drogemuller, C., Becker, D., Brunner, A., Haase, B., Kircher, P., Seeliger, F., Fehr, M., Baumann, U., Lindblad-Toh, K., Leeb, T. A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet. 5: e10000579, 2009. [PubMed: 19629171] [Full Text: https://doi.org/10.1371/journal.pgen.1000579]
Duran, I., Nevarez, L., Sarukhanov, A., Wu, S., Lee, K., Krejci, P., Weis, M., Eyre, D., Krakow, D., Cohn, D. H. HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum. Molec. Genet. 24: 1918-1928, 2015. [PubMed: 25510505] [Full Text: https://doi.org/10.1093/hmg/ddu608]
Hattori, T., Fujisawa, T., Sasaki, K., Yutani, Y., Nakanishi, T., Takahashi, K., Takigawa, M. Isolation and characterization of a rheumatoid arthritis-specific antigen (RA-A47) from a human chondrocytic cell line (HCS-2/8). Biochem. Biophys. Res. Commun. 245: 679-683, 1998. [PubMed: 9588174] [Full Text: https://doi.org/10.1006/bbrc.1998.8505]
Ikegawa, S., Nakamura, Y. Structure of the gene encoding human colligin-2 (CBP2). Gene 194: 301-303, 1997. [PubMed: 9272875] [Full Text: https://doi.org/10.1016/s0378-1119(97)00209-6]
Ikegawa, S., Sudo, K., Okui, K., Nakamura, Y. Isolation, characterization and chromosomal assignment of human colligin-2 gene (CBP2). Cytogenet. Cell Genet. 71: 182-186, 1995. [PubMed: 7656593] [Full Text: https://doi.org/10.1159/000134103]
Nagai, N., Tetuya, Y., Hosokawa, N., Nagata, K. The human genome has only one functional hsp47 gene (CBP2) and a pseudogene (pshsp47). Gene 227: 241-248, 1999. [PubMed: 10023073] [Full Text: https://doi.org/10.1016/s0378-1119(98)00592-7]
Tasab, M., Batten, M. R., Bulleid, N. J. Hsp47: a molecular chaperone that interacts with and stabilizes correctly-folded procollagen. EMBO J. 19: 2204-2211, 2000. [PubMed: 10811611] [Full Text: https://doi.org/10.1093/emboj/19.10.2204]
Thienel, M., Muller-Reif, J. B., Zhang, Z., Ehreiser, V., Huth, J., Shchurovska, K., Kilani, B., Schweizer, L., Geyer, P. E., Zwiebel, M., Novotny, J., Lusebrink, E., and 28 others. Immobility-associated thromboprotection is conserved across mammalian species from bear to human. Science 380: 178-187, 2023. [PubMed: 37053338] [Full Text: https://doi.org/10.1126/science.abo5044]
Wang, H., Parry, S., Macones, G., Sammel, M. D., Kuivaniemi, H., Tromp, G., Argyropoulos, G., Halder, I., Shriver, M. D., Romero, R., Strauss, J. F., III. A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans. Proc. Nat. Acad. Sci. 103: 13463-13467, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 19212 only, 2006. [PubMed: 16938879] [Full Text: https://doi.org/10.1073/pnas.0603676103]
Yasuda, K., Hirayoshi, K., Hirata, H., Kubota, H., Hosokawa, N., Nagata, K. The Kruppel-like factor Zf9 and proteins in the Sp1 family regulate the expression of HSP47, a collagen-specific molecular chaperone. J. Biol. Chem. 277: 44613-44622, 2002. [PubMed: 12235161] [Full Text: https://doi.org/10.1074/jbc.M208558200]