On this page
CTSC
cathepsin C
CTSC is located on the long (q) arm of chromosome 11, at band 11q14.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 11 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The CTSC gene provides instructions for making cathepsin C, also known as dipeptidyl peptidase I. This enzyme resides within lysosomes, membrane-bound compartments that break down cellular waste and foreign material. Cathepsin C serves a specialised role: it removes short amino-acid sequences from the ends of other proteins, thereby converting inactive precursors into functional enzymes. Many of these target proteins are serine proteases deployed by immune cells such as neutrophils and cytotoxic lymphocytes. When CTSC function is lost, these immune proteases remain inactive, impairing the body's ability to fight infections and maintain tissue integrity, particularly in the skin and gums.
What the gene does
Cathepsin C operates as a cysteine protease, using a catalytic cysteine residue to cleave peptide bonds. Its primary substrates include granzymes, neutrophil elastase, cathepsin G, and proteinase 3-enzymes stored in granules within immune cells. By removing dipeptide fragments from the N-terminus of these precursors, cathepsin C generates mature, active proteases that participate in antimicrobial defence and inflammatory responses. The enzyme assembles into a tetrameric complex, and this oligomeric structure appears necessary for efficient substrate processing. Beyond immune cells, cathepsin C is expressed in epithelial tissues, where its activity contributes to normal keratinocyte turnover and barrier function. Disruption of cathepsin C activity therefore has consequences for both immune surveillance and skin homeostasis, explaining the dual immunological and dermatological features observed when the gene is altered.
Video: Genetics 101
Chromosome location
CTSC is located on the long arm of chromosome 11 at band 11q14.2. The gene spans approximately 41 kilobases of genomic DNA and comprises multiple exons that encode a 463-amino-acid precursor protein. Following synthesis, the precursor undergoes proteolytic processing to yield the mature, catalytically active enzyme. The chromosomal region containing CTSC is relatively gene-dense, situated among other loci involved in metabolic and immune-related functions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. Cathepsin C is synthesised as a proenzyme containing an N-terminal propeptide, a catalytic domain with conserved cysteine-protease motifs, and an exclusion domain that determines substrate specificity. The mature enzyme assembles into a homotetramer, with each monomer contributing to the formation of active sites. This quaternary structure is thought to facilitate the enzyme's dipeptidase activity and regulate access to the catalytic pocket.
Key variants
Pathogenic variants in CTSC are inherited in an autosomal recessive pattern, meaning that affected individuals carry alterations in both gene copies. Variants include missense changes, small insertions or deletions, and nonsense mutations that introduce premature stop codons. Many reported variants cluster within the catalytic domain, disrupting the enzyme's ability to process substrates. Loss-of-function variants abolish cathepsin C activity, while some missense changes may permit residual function, potentially correlating with milder disease presentations.
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.1015C>T | p.Arg339Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Periodontitis, aggressive |
c.1141del | p.Leu381fs | Pathogenic | ★★☆☆ | Periodontitis, aggressive |
c.189del | p.Lys63_Val64insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Periodontitis, aggressive |
c.203T>G | p.Leu68Arg | Pathogenic/Likely pathogenic | ★★☆☆ | CTSC-related disorder |
c.319-1G>A | - | Pathogenic | ★★☆☆ | Periodontitis, aggressive |
c.415G>A | p.Gly139Arg | Pathogenic | ★★☆☆ | CTSC-related disorder |
c.566_572del | p.Thr189fs | Pathogenic | ★★☆☆ | CTSC-related disorder |
c.587T>C | p.Leu196Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Periodontitis, aggressive |
c.748C>T | p.Arg250Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CTSC-related disorder |
c.815G>A | p.Arg272His | Pathogenic/Likely pathogenic | ★★☆☆ | Periodontitis, aggressive |
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
Biallelic pathogenic variants in CTSC cause Papillon-Lefèvre syndrome, a rare autosomal recessive disorder characterised by severe periodontal disease beginning in early childhood and palmoplantar keratoderma-thickened, scaly skin on the palms and soles. Affected individuals typically experience premature loss of both primary and permanent teeth due to destruction of the periodontal ligament and alveolar bone. The skin manifestations usually appear within the first few years of life. Some individuals with CTSC variants present with related phenotypes, including isolated palmoplantar keratoderma or increased susceptibility to infections, reflecting the gene's dual roles in skin integrity and immune function.
Inheritance pattern
Conditions caused by pathogenic CTSC 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
CTSC is included on multiple NHS Genomic Medicine Service gene panels, reflecting its relevance to diverse clinical presentations. The gene appears on the Palmoplantar keratoderma and erythrokeratodermas panel and the Palmoplantar keratodermas panel (R166), supporting genetic testing for patients with thickened skin on the hands or feet. It is also listed on the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), acknowledging the immune consequences of cathepsin C deficiency. Additional memberships include the Likely inborn error of metabolism panel (R98) and the Skeletal dysplasia panel (R104), as well as research-focused panels such as COVID-19 research and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is Papillon-Lefèvre syndrome inherited?
Papillon-Lefèvre syndrome follows an autosomal recessive inheritance pattern. This means an individual must inherit a pathogenic CTSC variant from both parents to develop the condition. Parents who each carry one variant typically do not show symptoms.
Can genetic testing for CTSC help diagnose unexplained gum disease in children?
Yes, testing CTSC may be considered when a child presents with severe, early-onset periodontal disease, especially if accompanied by thickened skin on the palms or soles. Genetic confirmation can guide clinical management and inform family planning.
Are there treatments for conditions caused by CTSC variants?
Management focuses on supportive care, including aggressive dental hygiene, early periodontal intervention, and treatment of skin manifestations with topical keratolytic agents. Some patients may benefit from systemic retinoids. Genetic counselling is recommended for affected families.