Genomic coordinate ( human 11:88,265,069 CTSC).
Cytoband ( human 11q14.2 CTSC).
Here I 🎁 present: “Dipeptidyl-Peptidase-1 Pleiotropic Disorders, Victor McKusick, Mendelian Inheritance in Man’, 1966. (CTSC)
INTRODUCTION.
Dipeptidyl peptidase-1 (DPP1), also known as cathepsin C, is a vital enzyme primarily responsible for activating neutrophil serine proteases (NSPs). Pleiotropic disorders associated with DPP1 often stem from genetic mutations leading to a total loss of enzyme function, or they relate to its broad role in regulating inflammation across multiple organ systems.
Key Genetic Pleiotropic Disorders.
Biallelic loss-of-function mutations in the CTSC gene (which encodes DPP1) lead to rare autosomal recessive disorders characterized by a combination of dermatological and dental symptoms.
Papillon-Lefèvre Syndrome (PLS): This is the most well-known disorder. It typically manifests with palmoplantar hyperkeratosis (thickening of the skin on palms and soles) and severe, early-onset periodontitis, often resulting in the premature loss of both primary and permanent teeth. Despite the near-total loss of NSP activity, patients generally maintain normal resistance to systemic infections.
Haim-Munk Syndrome: Closely related to PLS, this syndrome shares the symptoms of hyperkeratosis and periodontitis but includes additional skeletal and nail abnormalities like onychogryphosis (curved nails), pes planus (flat feet), and arachnodactyly (long, slender fingers).
Pleiotropic Role in Inflammatory Diseases
Because DPP1 is a central “upstream” activator of inflammatory enzymes like neutrophil elastase and proteinase 3, it is implicated in various chronic inflammatory conditions beyond its primary function.
Respiratory Conditions: Elevated DPP1 activity is linked to tissue destruction in bronchiectasis, COPD, and cystic fibrosis. Researchers are developing DPP1 inhibitors like brensocatib to treat these by reducing the “downstream” damage caused by NSPs.
Immune Regulation: DPP1 is involved in the maturation of granzymes in natural killer cells and T-lymphocytes, which are essential for clearing infected or cancerous cells.
Cardiovascular Effects: While more commonly discussed regarding its “cousin” enzyme DPP4, DPP1’s role in neutrophil-mediated inflammation can impact plaque stability in atherosclerosis.
Comparative Context: DPP1 vs. DPP4
It is important to distinguish between DPP1 and the more widely known DPP4, which is a primary target for diabetes medications. While DPP4 inhibitors are used for glycemic control, they also exhibit pleiotropic cardiovascular benefits by improving endothelial function and reducing inflammation. In contrast, the pleiotropic benefits of DPP-4 inhibitors beyond glycemic control are frequently studied for their effects on vascular senescence and renal protection.
