Loss-of-function mutations in cathepsin C in two families with Papillon-Lefèvre syndrome are associated with deficiency of serine proteinases in PMNs

Abstract

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disease that involves severe periodontitis and hyperkeratosis of the hand palms and foot soles. Recently it was found that PLS patients carry loss-of-function mutations in the gene encoding cathepsin C (CTSC). In the present study we have analyzed the CTSC gene in two unrelated families with PLS. In the first non-consanguineous family, mutation analysis revealed the previously reported c.815G>C/p.R272P mutation. The second consanguineous family displayed a c.1213C>A mutation which resulted in the novel mutation p.H405N and is the first mutation described in the active site of the enzyme. The PLS patients had, next to the absence of cathepsin C activity in polymorphonuclear leukocytes (PMNs), no activity of the three serine proteinases elastase, cathepsin G and proteinase 3. Serine proteinases are supposed to be important in both the innate and adaptive immune systems. Their absence in PLS patients could explain the inadequate defense to periodontal infection.

Role of Polymorphonuclear Leukocyte-Derived Serine Proteinases in Defense againstActinobacillus actinomycetemcomitans

“…The patients showed no cathepsin C activity, and the mother had reduced (50%) levels. We confirmed that the patients were deficient for elastase, cathepsin G, and proteinase 3 activity (16).…”

“…Genomic DNA was isolated from the blood samples by using the Puregene kit (Gentra Systems, Inc., Michigan) according to the manufacturer's protocol. Sequencing was performed as described previously (16). In family C, a previously reported mutation, c.815GϾC/p.R272P, was found (72).…”

“…Recently, we showed that cathepsin C is the activator of the PMN-derived serine proteinases elastase, cathepsin G, and proteinase 3 in human (16). The absence of cathepsin C not only leads to a loss of activity of the serine proteinases in PMNs of PLS patients but also to a reduction in the amount of the proteins themselves.…”

Neutrophil extracellular traps — the dark side of neutrophils

“…This enzyme is required for removal of two N-terminal amino acids that block the active site of neutrophil serine proteases (62). Failure to remove these two N-terminal amino acids results in the inability to generate active enzyme and complete degradation of the serine proteases before mature neutrophils are formed (11,63,64). These patients are therefore completely devoid of all neutrophil serine proteases, including elastase, and hence incapable of generating NETs (11), except by saliva (18).…”

Cathepsin H Is an Additional Convertase of Pro-granzyme B

“…First, activated lymphocytes derived from humans with congenital deficiency of CatC (PapillonLefevre syndrome) contain active GrB and kill target cells with similar efficiency to healthy controls (10). Papillon-Lefevre syndrome patients present principally with manifestations of neutrophil dysfunction, such as severe gingivitis, because the neutrophil serine proteases cathepsin G and elastase depend completely on CatC for processing (10,11). Secondly, lymphocytes from CatC Ϫ/Ϫ mice possess active GrB and kill target cells almost as efficiently as wild-type mice (12).…”