Abstract

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.

Highlights

  • Neutrophil granulocytes are phagocytic white blood cells that are critical components of the inflammatory process and fight against invading pathogens

  • A genetic analysis was performed, and the patients of family A (PLS 1 and 2) were found homozygous for the gene variant GCF_000001405.13(CTSC):g.88042469T>C, c.503A>G, p. (Tyr168Cys). This is a variation at position 88042469 leading to a 503A>G substitution in exon 4 of the Cathepsin C (CTSC) gene, which is expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein

  • This substitution was predicted to be deleterious for protein function by the Polyphen2 HDIV, Polyphen2 HVAR, LRT, MutationTaster and FATHMM method, among others. This mutation is rare with only sporadic heterozygote individuals reported, giving rise to different allele frequencies in different databases; gnomAD: C = 0.000032/1 [43], TOPMed: C = 0.000016/2 [44], and no reports in ALFA [45]. We only found this genetic variant entered in genetic databases for heterozygous carriers, and to the best of our knowledge, data of only one patient with Papillon-Lefèvre Syndrome (PLS) homozygous for 503A>G has been previously published by Sørensen et al [9] without submission to genetic databases

Read more

Summary

Introduction

Neutrophil granulocytes are phagocytic white blood cells that are critical components of the inflammatory process and fight against invading pathogens They are loaded with a wide variety of antimicrobial compounds and proteolytic enzymes that contribute to microbial killing and risk damaging endogenous tissues if not properly regulated [1]. Patients with chronic granulomatous disease (CGD) are plagued by infections and by a variety of, often aseptic, inflammatory disorders [3, 4]. This indicates that neutrophils are critical microbial killers but that they are important regulators of inflammatory processes

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call