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PPIB
peptidylprolyl isomerase B
PPIB is located on the long (q) arm of chromosome 15, at band 15q22.31. Arm ratio per GRCh38 - banding schematic.
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Overview
PPIB is located on chromosome 15 and encodes cyclophilin B, a member of the peptidylprolyl isomerase family. These enzymes catalyse the conversion of peptide bonds between proline residues, a critical step in protein folding. Cyclophilin B functions primarily within the endoplasmic reticulum, the cellular compartment where newly synthesised proteins are folded and assembled.
The protein is particularly important for collagen biosynthesis, where it assists in the folding of procollagen chains before they are secreted from cells. Because collagen is the most abundant structural protein in the human body, forming the framework of bones, tendons, skin, and blood vessels, proper cyclophilin B function is essential for skeletal development and connective tissue integrity. Disruption of PPIB function can therefore have widespread effects on tissues that rely on collagen for structural support.
What the gene does
Cyclophilin B functions as a peptidylprolyl cis-trans isomerase, an enzyme class that accelerates the rotation of peptide bonds preceding proline residues during protein folding. This activity is particularly important for collagen molecules, which contain repeating sequences rich in proline and hydroxyproline residues. The enzyme facilitates the proper three-dimensional folding of procollagen chains, enabling three individual chains to align correctly and form the characteristic triple helix structure.
The protein operates within the endoplasmic reticulum lumen, where it interacts with nascent collagen chains as they are synthesised. By catalysing the isomerisation of proline-containing peptide bonds, cyclophilin B helps ensure that collagen molecules adopt the correct conformation required for subsequent processing steps. This includes the formation of cross-links between collagen molecules, which provide tensile strength to connective tissues. The enzyme's activity is therefore essential for producing collagen with appropriate structural properties to support skeletal integrity and tissue resilience.
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Chromosome location
PPIB is located on the long arm of chromosome 15 at position 22.31 (15q22.31). The gene spans approximately 8 kilobases of genomic DNA and contains seven exons. This chromosomal region contains several other genes involved in cellular metabolism and protein processing, though PPIB itself appears to function independently of its neighbouring genes.
Protein structure
The cyclophilin B protein comprises 216 amino acids and contains two key structural features. The PPIase cyclophilin-type domain extends from amino acids 47 to 204 and constitutes the catalytic core of the enzyme, responsible for its peptidylprolyl isomerase activity. This domain adopts a characteristic beta-barrel structure that forms the active site where proline-containing peptide substrates bind and undergo isomerisation. The Prevents secretion from ER motif, located at amino acids 213 to 216 at the C-terminus, functions as an endoplasmic reticulum retention signal. This motif ensures that cyclophilin B remains localised within the endoplasmic reticulum lumen rather than being secreted from the cell, maintaining its availability for assisting protein folding in the appropriate cellular compartment.
Key variants
Pathogenic variants in PPIB follow an autosomal recessive inheritance pattern, meaning that affected individuals typically carry two altered copies of the gene, one inherited from each parent. Parents who carry a single pathogenic variant are generally unaffected but have a 25% chance with each pregnancy of having a child with two variants. Most reported pathogenic changes are missense variants that alter single amino acids within the catalytic domain, reducing or abolishing the enzyme's ability to facilitate collagen folding.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in PPIB cause osteogenesis imperfecta type IX, a form of brittle bone disease characterised by skeletal fragility and increased fracture susceptibility. Affected individuals typically present with bone deformities, reduced bone mineral density, and fractures that may occur with minimal trauma or even spontaneously. The severity can vary, with some individuals experiencing frequent fractures from infancy whilst others have a milder presentation with fractures beginning in childhood. Additional features may include short stature, blue sclerae (a bluish tint to the whites of the eyes), and dental abnormalities. The condition results from defective collagen assembly due to impaired cyclophilin B function, compromising the structural integrity of bone tissue.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PPIB variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
Within the NHS Genomic Medicine Service, PPIB is included on multiple clinical gene panels with green (high evidence) classification. The gene appears on the Fetal anomalies panel (version R21) for prenatal genomic investigations, the Osteogenesis imperfecta panel (version R102) for targeted assessment of inherited bone fragility disorders, and the Skeletal dysplasia panel (version R104) for broader evaluation of conditions affecting skeletal development. These panel inclusions reflect the established clinical validity of PPIB testing in the diagnostic pathway for individuals presenting with unexplained skeletal fragility or abnormalities detected during pregnancy.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is PPIB-related osteogenesis imperfecta inherited?
PPIB-related osteogenesis imperfecta follows autosomal recessive inheritance, meaning both copies of the gene must carry pathogenic variants for the condition to develop. Parents who each carry one variant typically have no symptoms but have a 25% chance with each pregnancy of having an affected child.
What is the role of cyclophilin B in collagen production?
Cyclophilin B is a folding enzyme that assists in the proper assembly of collagen molecules within the endoplasmic reticulum. It catalyses the rotation of peptide bonds near proline residues, helping collagen chains fold correctly and form the triple helix structure required for strong, functional connective tissue.
Can PPIB variants affect tissues other than bone?
Whilst skeletal manifestations are the primary feature of PPIB-related conditions, collagen is present throughout the body in skin, blood vessels, and other connective tissues. Some individuals may experience additional features such as dental abnormalities or joint hypermobility, though bone fragility remains the most clinically significant aspect of the condition.