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SERPINF1
serpin family F member 1
SERPINF1 is located on the short (p) arm of chromosome 17, at band 17p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
SERPINF1 is located on chromosome 17 and contains the instructions for producing pigment epithelium-derived factor (PEDF), a multifunctional protein first identified in retinal cells but now known to be active throughout the body. Despite belonging to the serpin (serine protease inhibitor) family, PEDF does not inhibit proteases. Instead, it functions as a secreted signalling molecule with diverse biological activities.
Pathogenic variants in SERPINF1 follow an autosomal recessive inheritance pattern, meaning that a condition manifests only when an individual inherits altered copies from both parents. Changes in this gene are primarily associated with bone fragility disorders, particularly osteogenesis imperfecta type VI, a rare form of brittle bone disease characterised by moderately severe bone fragility and distinctive biochemical features.
What the gene does
Pigment epithelium-derived factor operates as a secreted glycoprotein with several distinct biological functions. In bone tissue, PEDF appears to regulate the balance between bone formation and breakdown, interacting with cells that build bone (osteoblasts) and influencing the maturation of bone mineral. The protein also exhibits potent anti-angiogenic properties, meaning it can inhibit the formation of new blood vessels, a function that has attracted research interest in cancer biology and eye disease.
Beyond its skeletal and vascular roles, PEDF demonstrates neuroprotective and anti-inflammatory activities. The protein can promote neuronal survival under stress conditions and modulate immune responses in various tissues. These diverse functions suggest that PEDF acts as a tissue-protective factor, helping to maintain cellular health and tissue architecture across multiple organ systems. The protein's activity depends on its secretion into the extracellular space, where it can interact with cell-surface receptors and influence cellular behaviour through downstream signalling pathways.
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Chromosome location
SERPINF1 is located on the short arm of chromosome 17 at position 17p13.3. This chromosomal region lies near the telomere (end) of chromosome 17's short arm and contains several other genes involved in development and cellular regulation. The gene spans approximately 15 kilobases of genomic DNA and comprises eight exons that are transcribed and processed to produce the mature messenger RNA template for PEDF synthesis.
Protein structure
The SERPINF1 protein consists of 418 amino acids with a molecular architecture typical of the serpin superfamily, featuring a characteristic three-beta-sheet structure. However, PEDF has diverged functionally from classic serpins and lacks the reactive centre loop that would enable protease inhibition.
The protein contains a disordered region spanning amino acids 20 to 39, which may provide structural flexibility important for protein-protein interactions or conformational changes. Near the C-terminus, a region from amino acids 371 to 383 undergoes O-glycosylation at one site, a post-translational modification that adds carbohydrate groups to specific amino acid residues. This glycosylation may influence protein stability, secretion, or interaction with cellular receptors. The mature protein also includes an N-terminal signal peptide that directs PEDF for secretion from cells into the extracellular environment.
Key variants
Genetic variants in SERPINF1 that disrupt normal protein function are relatively uncommon but clinically significant when present. Most pathogenic changes reported in this gene are either nonsense variants that introduce premature stop signals, frameshift variants caused by small insertions or deletions, or missense variants that alter critical amino acid residues required for protein folding or function. The recessive inheritance pattern means that individuals carrying one altered copy alongside one functional copy typically do not show clinical features, whilst those with variants affecting both gene copies may develop skeletal abnormalities.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1217_1253del | p.Leu406fs | Pathogenic/Likely pathogenic | ★★☆☆ | SERPINF1-related disorder |
c.295C>T | p.Arg99Ter | Pathogenic | ★★☆☆ | Osteogenesis imperfecta |
c.498_499del | p.Arg167fs | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.532C>T | p.Gln178Ter | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.553C>T | p.Gln185Ter | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.77del | p.Pro26fs | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.77dup | p.Glu27fs | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.808G>T | p.Gly270Ter | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 6 |
c.857_868del | p.Leu286_Glu290delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | SERPINF1-related disorder |
c.907C>T | p.Arg303Ter | Pathogenic/Likely pathogenic | ★★☆☆ | SERPINF1-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in SERPINF1 are primarily associated with osteogenesis imperfecta type VI, an autosomal recessive form of brittle bone disease. Individuals with this condition typically experience moderate to severe bone fragility, leading to recurrent fractures that may begin in infancy or early childhood. Unlike some other types of osteogenesis imperfecta, type VI shows distinctive features including elevated alkaline phosphatase levels and characteristic findings on bone biopsy revealing a fish-scale pattern of bone lamellation.
The skeletal manifestations can include vertebral compression fractures, long bone deformities, and reduced bone mineral density. Despite the significant skeletal involvement, many affected individuals have normal or near-normal stature and do not show the blue sclera (bluish tint to the whites of the eyes) often seen in other osteogenesis imperfecta types. The condition's severity can vary between individuals, even among those with similar genetic variants.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SERPINF1 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 UK National Health Service Genomic Medicine Service, SERPINF1 appears on several clinical gene panels used to guide testing for skeletal conditions. The gene holds green (high evidence) classification on the Fetal Anomalies panel, the Osteogenesis Imperfecta panel, and the Skeletal Dysplasia panel. This green rating indicates strong evidence supporting the gene-disease relationship and reflects consensus among clinical experts that SERPINF1 testing is appropriate when evaluating individuals with features consistent with these conditions. Inclusion on the Fetal Anomalies panel reflects the potential for prenatal detection of skeletal abnormalities in affected pregnancies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is SERPINF1 inherited?
SERPINF1-related conditions follow an autosomal recessive pattern. This means an individual must inherit an altered copy of the gene from both parents to develop the condition. People with one altered copy are carriers and typically do not show symptoms.
What makes osteogenesis imperfecta type VI different from other types?
Type VI, caused by SERPINF1 variants, is distinguished by elevated alkaline phosphatase levels, a characteristic fish-scale pattern seen on bone biopsy, and moderate to severe bone fragility without the blue sclera commonly seen in other osteogenesis imperfecta types. It is also one of the rarer autosomal recessive forms.
Why doesn't PEDF function as a protease inhibitor despite being a serpin?
Although PEDF belongs to the serpin superfamily, it has evolved to lose the reactive centre loop structure that enables other serpins to inhibit proteases. Instead, PEDF has acquired distinct functions in angiogenesis regulation, neuroprotection, and bone metabolism through different structural features.