Alternative titles; symbols
HGNC Approved Gene Symbol: PPIB
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38): 15:64,155,817-64,163,022 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.31 | Osteogenesis imperfecta, type IX | 259440 | Autosomal recessive | 3 |
Cyclophilins, such as CYPB, bind the immunosuppressive drug cyclosporin A (CsA) with high affinity. CsA blocks helper T-cell activation at a step between T-cell receptor stimulation and the transcriptional activation of cytokine genes. Cyclophilins from many species possess peptidyl-prolyl cis-trans isomerase (PPIase) activity that is blocked by CsA and therefore may be relevant in CsA-mediated immunosuppression (Price et al., 1991).
Probing with the cyclophilin A (CYPA; 123840) cDNA under reduced stringencies, Price et al. (1991) identified the CYPB gene. The deduced protein is 64% identical to CYPA and is distinguished from it by a signal sequence that probably directs it to the endoplasmic reticulum (ER). CYPB shows even stronger similarity to yeast CYPB, which also has an ER-directed signal sequence.
Peddada et al. (1992) used the PCR technique to generate a unique probe complementary to the hydrophobic 5-prime end of the human cyclophilin B gene. Using this probe in an analysis of human/hamster hybrid somatic cell lines, they assigned the CYPB gene to chromosome 15.
Price et al. (1991) found that the signal sequence was removed from CYPB upon expression in E. coli, and the processed protein possessed PPIase activity that was inhibited by CsA.
Yurchenko et al. (2001) determined that CD147 (BSG; 109480) serves as a receptor for CYPB. CYPB induced Ca(2+) flux, ERK (see MAPK3; 601795) phosphorylation, and chemotaxis in CD147-transfected Chinese hamster ovary cells, but not in control cells. The chemotactic response of primary human neutrophils to CYPB was blocked by antibodies to CD147.
FHOD1 (606881) regulates gene transcription, actin-cytoskeleton structure, and cell migration. Using a yeast 2-hybrid screen with a human bone marrow cDNA expression library, Westendorf and Koka (2004) found that FHOD1 interacted with cyclophilin B, as well as with the central portion of PRKCBP1 (ZMYND8; 615713) and the B isoform of WISH (NCKIPSD; 606671).
Using CsA as a bioprobe to identify cellular factors involved in hepatitis C virus (HCV) genome replication, Watashi et al. (2005) showed that CYPB interacts with HCV RNA polymerase NS5B to directly stimulate its RNA binding activity. HCV replication could be reduced by RNA interference-mediated reduction of endogenous CYPB expression or by the induced loss of NS5B binding to CYPB. Watashi et al. (2005) concluded that CYPB functions as a stimulatory regulator of NS5B in the HCV replication machinery and suggested that CYPB could be a target for antiviral therapy.
CRTAP (605497), P3H1 (LEPRE1; 610339), and CYPB (PPIB) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the alpha-1 chains of collagen type I (120150), and deficiency of CRTAP or P3H1 has been reported in autosomal recessive lethal or severe osteogenesis imperfecta (OI; see 610682 and 610915). In 4 patients with osteogenesis imperfecta type IX (OI9; 259440) from 2 unrelated families, van Dijk et al. (2009) analyzed the PPIB gene and identified homozygosity for a 4-bp deletion (123841.0001) and a nonsense mutation (123841.0002), respectively. The percentage of 3-hydroxylated P986 residues in patients with PPIB mutations was decreased in comparison to controls, but it was higher than in patients with CRTAP or LEPRE1 mutations. In addition, in bone tissue from patients with CRTAP or LEPRE1 mutations, CYPB was detected but both CRTAP and P3H1 were absent, indicating that CYPB is independent of the presence of either CRTAP or P3H1. Van Dijk et al. (2009) suggested that recessive OI is caused by a dysfunctional P3H1/CRTAP/CYPB complex rather than by lack of 3-prolyl hydroxylation of a single proline residue in the alpha-1 chains of collagen type I.
In a sister and brother who had moderately severe osteogenesis imperfecta without rhizomelia, who were born of consanguineous Senegalese parents, Barnes et al. (2010) identified homozygosity for a missense mutation in the PPIB gene (123841.0003). The proband had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CYPB is not the exclusive peptidyl-prolyl cis-trans isomerase that catalyzes the rate-limiting step in collagen folding.
In a Palestinian pedigree segregating moderate and lethal forms of OI, Barnes et al. (2012) identified a homozygous indel mutation in the FKBP10 gene (607063.0009) in a proband from one branch of the family with OI type 11 (610968), and a homozygous deletion in the PPIB gene (123841.0004) in a proband from another branch of the family with OI type IX (259440).
Pyott et al. (2011) identified mutations in the PPIB gene in 3 families with OI9; one family had a lethal OI type II phenotype, another had a severe OI type III phenotype, and the last had a moderately severe deforming OI type III/IV phenotype. Two sibs with the lethal form had compound heterozygous mutations: a deletion (123841.0005) inherited from their mother and a missense mutation (123841.0006) inherited from their father.
Hereditary equine regional dermal asthenia (HERDA) is a degenerative skin disease that affects the Quarter Horse breed. Tryon et al. (2007) determined that HERDA is due to a missense mutation (gly39 to arg) in the equine Ppib gene that alters a glycine conserved across vertebrates. The mutation was homozygous in 64 affected horses and segregated concordant with inbreeding loops in the genealogy of 11 affected horses. Screening of control Quarter Horses indicated a 3.5% carrier frequency.
In 2 fetuses with osteogenesis imperfecta type IX (OI9; 259440) from a nonconsanguineous northern European family, van Dijk et al. (2009) identified homozygosity for a 4-bp deletion (556delAAGA) in exon 5 of the PPIB gene, resulting in a frameshift that replaces 31 highly conserved C-terminal residues and causes a premature stop in the last exon (Lys186GlnfsTer8). The unaffected parents were heterozygous carriers of the deletion, which was not found in 192 control alleles.
In 2 sibs with osteogenesis imperfecta type IX (OI9; 259440) from a consanguineous Pakistani family, van Dijk et al. (2009) identified homozygosity for a 451C-T transition in exon 4 of the PPIB gene, resulting in a gln151-to-ter (Q151X) substitution that removes the last 65 residues at the C terminus. The unaffected parents were heterozygous carriers of the deletion, which was not found in 192 control alleles.
In a sister and brother who had moderately severe osteogenesis imperfecta without rhizomelia (OI9; 259440), Barnes et al. (2010) identified homozygosity for what they designated a 2T-G transversion, predicted to eliminate the start codon of the PPIB gene. Van Dijk et al. (2010) stated that using the current PPIB reference sequence (NM_000942.4), this is a 26T-G transversion resulting in a met9-to-arg (M9R) substitution, which could account for the relatively milder phenotype. Using RT-PCR analysis, Barnes et al. (2010) found that PPIB transcripts in the proband were approximately 55% of normal; CYPB protein was undetectable in the proband fibroblast lysate or on immunofluorescence staining of fibroblasts. The proband's type I collagen showed normal modification and folding. The unaffected consanguineous Senegalese parents were heterozygous for the mutation, as were unaffected sibs.
In a Palestinian pedigree segregating moderate and lethal forms of recessive OI, Barnes et al. (2012) identified in one pedigree branch a homozygous deletion in the PPIB gene (563_566delACAG) in 2 children with lethal type IX OI (OI9; 259440); in another branch, they identified a homozygous FKBP10 indel mutation (607063.0009) in a child with moderate type XI OI (610968).
In 2 sibs with a lethal form of OI (OI9; 259440), Pyott et al. (2011) identified compound heterozygous mutations in the PPIB gene: a maternally derived 1-bp deletion (c.120delC) that resulted in a frameshift, a premature termination codon (Val42SerfsTer16), and nonsense-mediated mRNA decay, and a paternally derived c.313G-A transition that resulted in a gly105-to-arg (G105R; 123841.0006) substitution. The protein synthesized from the second allele was unstable, and at least some of the small amount of remaining protein was mislocalized to the Golgi.
For discussion of the c.313G-A transition in the PPIB gene, resulting in a gly105-to-arg (G105R) substitution, that was found in compound heterozygous state in 2 sibs with a lethal form of OI (OI9; 259440), see 123841.0005.
Barnes, A. M., Cabral, W. A., Weis, M., Makareeva, E., Mertz, E. L., Leikin, S., Eyre, D., Trujillo, C., Marini, J. C. Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix. Hum. Mutat. 33: 1589-1598, 2012. [PubMed: 22718341] [Full Text: https://doi.org/10.1002/humu.22139]
Barnes, A. M., Carter, E. M., Cabral, W. A., Weis, M., Chang, W., Makareeva, E., Leikin, S., Rotimi, C. N., Eyre, D. R., Raggio, C. L., Marini, J. C. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. New Eng. J. Med. 362: 521-528, 2010. [PubMed: 20089953] [Full Text: https://doi.org/10.1056/NEJMoa0907705]
Peddada, L. B., McPherson, J. D., Law, R., Wasmuth, J. J., Youderian, P., Deans, R. J. Somatic cell mapping of the human cyclophilin B gene (PPIB) to chromosome 15. Cytogenet. Cell Genet. 60: 219-221, 1992. [PubMed: 1505219] [Full Text: https://doi.org/10.1159/000133343]
Price, E. R., Zydowsky, L. D., Jin, M., Baker, C. H., McKeon, F. D., Walsh, C. T. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc. Nat. Acad. Sci. 88: 1903-1907, 1991. [PubMed: 2000394] [Full Text: https://doi.org/10.1073/pnas.88.5.1903]
Pyott, S. M., Schwarze, U., Christiansen, H. E., Pepin, M. G., Leistritz, D. F., Dineen, R., Harris, C., Burton, B. K., Angle, B., Kim, K., Sussman, M. D., Weis, M. A., Eyre, D. R., Russell, D. W., McCarthy, K. J., Steiner, R. D., Byers, P. H. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Hum. Molec. Genet. 20: 1595-1609, 2011. [PubMed: 21282188] [Full Text: https://doi.org/10.1093/hmg/ddr037]
Tryon, R. C., White, S. D., Bannasch, D. L. Homozygosity mapping approach identifies a missense mutation in equine cyclophilin B (PPIB) associated with HERDA in the American Quarter Horse. Genomics 90: 93-102, 2007. [PubMed: 17498917] [Full Text: https://doi.org/10.1016/j.ygeno.2007.03.009]
van Dijk, F. S., Cobben, J. M., Pals, G. Osteogenesis imperfecta, normal collagen folding, and lack of cyclophilin B. (Letter) New Eng. J. Med. 362: 1940-1941, 2010. [PubMed: 20484404] [Full Text: https://doi.org/10.1056/NEJMc1002797]
van Dijk, F. S., Nesbitt, I. M., Zwikstra, E. H., Nikkels, P. G. J., Piersma, S. R., Fratantoni, S. A., Jimenez, C. R., Huizer, M., Morsman, A. C., Cobben, J. M., van Roij, M. H. H., Elting, M. W., and 9 others. PPIB mutations cause severe osteogenesis imperfecta. Am. J. Hum. Genet. 85: 521-527, 2009. [PubMed: 19781681] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.001]
Watashi, K., Ishii, N., Hijikata, M., Inoue, D., Murata, T., Miyanari, Y., Shimotohno, K. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Molec. Cell 19: 111-122, 2005. [PubMed: 15989969] [Full Text: https://doi.org/10.1016/j.molcel.2005.05.014]
Westendorf, J. J., Koka, S. Identification of FHOD1-binding proteins and mechanisms of FHOD1-regulated actin dynamics. J. Cell. Biochem. 92: 29-41, 2004. [PubMed: 15095401] [Full Text: https://doi.org/10.1002/jcb.20031]
Yurchenko, V., O'Connor, M., Dai, W. W., Guo, H., Toole, B., Sherry, B., Bukrinsky, M. CD147 is a signaling receptor for cyclophilin B. Biochem. Biophys. Res. Commun. 288: 786-788, 2001. [PubMed: 11688976] [Full Text: https://doi.org/10.1006/bbrc.2001.5847]