Alternative titles; symbolsCYCLOPHILIN D; CYPDCYCLOPHILIN 40; CYP40HGNC Approved Gene Symbol: PPIDCytogenetic location: 4q32.1 Genomic coordinates (GRCh38): ...
Alternative titles; symbols
HGNC Approved Gene Symbol: PPID
Cytogenetic location: 4q32.1 Genomic coordinates (GRCh38): 4:158,709,126-158,723,395 (from NCBI)
PPID is an integral constituent of the mitochondrial permeability transition pore that is induced in response to the release of calcium from endoplasmic reticulum stores. Apoptotic stimuli induce pore activation, resulting in cytochrome c release from mitochondrial intermembrane space and initiation of the apoptotic cascade. Sustained opening of these pores allows equilibrium of ions between the mitochondrial matrix and cytoplasm and dissipation of the inner membrane potential (summary by Yasuda et al., 2006).
▼ Cloning and Expression
The cyclophilins are a conserved gene family of peptidyl-prolyl cis-trans isomerases (PPIases; see 123840), the members of which bind the immunosuppressant cyclosporin A. Cyclophilin-40 (CyP40, also CYPD) was identified by Kieffer et al. (1992) as a 40-kD cyclophilin-like protein with PPIase activity. In the bovine uterus, CyP40 is a component of the estrogen receptor complex (see 133430). Kieffer et al. (1993) reported the cloning of a human cDNA homologous to the bovine CyP40. The cDNA encodes a predicted 370-amino acid protein. The amino end is similar to that of other cyclophilins, while the carboxyl region resembles FKBP59 (600611), a component of the glucocorticoid receptor complex.
▼ Gene Structure
Yokoi et al. (1996) showed that the cyclophilin-40 (or PPID) gene contains 10 exons and spans 14.2 kb of genomic DNA. Ten Alu repeats occur within noncoding regions of the gene.
Yokoi et al. (1996) mapped the PPID gene to chromosome 4 using a panel of somatic cell hybrid DNAs. By fluorescence in situ hybridization, Ratajczak et al. (1997) mapped the PPID gene to chromosome 4q31.3.
▼ Gene Function
Yasuda et al. (2006) found that overexpression of mouse Apop1 (APOPT1; 616003) in mouse and human cells caused cell death via release of cytochrome c from mitochondria and activation of caspase-9 (CASP9; 602234) and caspase-3 (CASP3; 600636). Apop1-induced apoptosis was blocked by cyclosporin A, an inhibitor of the permeability transition pore, but not by inhibitors of Bax (600040)/Bak (BAK1; 600516)-dependent channels. Hepatocytes cultured from mice deficient in cyclophilin D were resistant to Apop1-induced cell death. Yasuda et al. (2006) concluded that cyclophilin D functions in apoptotic signaling in a manner similar to, but distinct from, BAX-BAK channels.
▼ Animal Model
Palma et al. (2009) showed that inactivation of the Ppid gene rescued the disease phenotype of Col6a1 (120220) deficiency. In the absence of CypD, Col6a1-null mice showed negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis. Palma et al. (2009) concluded that lack of CypD is equivalent to its inhibition with cyclosporin A at curing the mouse dystrophic phenotype and that there is a cause and effect relationship between CypD-dependent permeability transition pore (PTP) regulation and pathogenesis of Bethlem myopathy (see 158810) and UCMD (see 254090), suggesting CypD and PTP as a pharmacologic target for therapy.
Confusion exists in the literature between cyclophilin D and cyclophilin F (604486). The designation cyclophilin D (CypD) has been used in mouse and rat for the gene product of both the Ppid and the Ppif genes.