Papillon–Lefèvre syndrome (PLS) with novel compound heterozygous mutation in the exclusion and Peptidase C1A domains of Cathepsin C gene


Papillon Lefevre syndrome (PLS) manifests with palmoplantar keratoderma, combined with a rapidly progressive periodontitis associated with mutations in Cathepsin C (CTSC) gene. This article reports a 15-year old male proband with typical PLS traits having a novel compound heterozygote with p.Q49X mutation in exon 1 and p.Y259C missense mutation in exon 6 of CTSC gene respectively. The exon 1 mutation, p.Q49X, (found in proband’s mother) was located in exclusion domain and exon 6 mutation, p.Y259C (found in proband’s father), was present in peptidase C1A, papain C-terminal domain. Interestingly, missense mutation p.Y259C identified in this study was found to be not reported so far. Upon computational analysis, this missense mutation was found to be lethal. Moreover, our protein modelling approach using mutant protein revealed the presence of monomeric structure on contrary to the tetrameric structure of the wild type protein. In addition, in vitro functional characterization of mutant p.Y259C expressed in HEK293 cells showed a significant reduction in CTSC activity (0.015 ± 0.009 mU/ml) when compared with wild type protein (0.21 ± 0.008 mU/ml). Thus, in this study, we have demonstrated that the pathogenic missense mutant p.Y259C might cause PLS by impaired CTSC function.

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Papillon lefevre syndrome


Cathepsin C


  1. 1.

    Papillon MN, Lefevre B (1924) Two cases of familial symmetric palmoplanter keratosis (Maleda’s disease) in a brother and his sister. Alterations in both cases (in French). Bull Soc Francaise Dermatologie Syphiligraphie 31:81–84

    Google Scholar 

  2. 2.

    Fageeh HN (2018) Papillon-Lefèvre syndrome: a rare case report of two brothers and review of the literature. Int J Clin Pediatr Dent 1:352–355.

    Article  Google Scholar 

  3. 3.

    Korkmaz B, Caughey GH, Chapple I et al (2018) Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Pharmacol Ther 190:202–236.

    Article  PubMed  Google Scholar 

  4. 4.

    Hart TC, Bowden DW, Ghaffar KA, Wang W, Cutler CW, Cebeci I et al (1998) Sublocalization of the Papillon-Lefevre syndrome on chromosome 11q14-q21. Am J Med Genet 79(19980901):134–139

    CAS  Article  Google Scholar 

  5. 5.

    Lingeswaran A, Gopal SD (2018) A rare presentation of psychotic depression with suicidality in a case of papillon–lefèvre syndrome. Indian J Psychol Med 40:372–374

    Article  Google Scholar 

  6. 6.

    Toomes C, James J, Wood AJ, McCormick D, Lench N, Hewitt CH et al (1999) Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:421–424.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Chedid JA, Salameh M, El-Outa A, Noujeim ZEF (2019) Papillon-Lefèvre Syndrome: diagnosis, dental management, and a case report. Case Rep Dent.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bullón P, Castejón-Vega B, Román-Malo L et al (2018) Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment. J Allergy Clin Immunol 142:1131–1143

    Article  Google Scholar 

  9. 9.

    Hattab FN (2019) Papillon-Lefèvre syndrome: from then until now. Stomatol Dis Sci 3:1.

    Article  Google Scholar 

  10. 10.

    Allende LM, García-Pérez MA, Moreno A, Corell A, Carasol M, Martínez-Canut P et al (2001) Cathepsin C gene: first compound heterozygous patient with Papillon-Lefèvre syndrome and a novel symptomless mutation. Hum Mutat 17:152–153

    CAS  Article  Google Scholar 

  11. 11.

    Selvaraju V, Markandaya M, Prasad PV, Sathyan P, Sethuraman G, Srivastava SC (2003) Mutation analysis of the cathepsin C gene in Indian families with Papillon-Lefèvre syndrome. BMC Med Genet 4:5.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Rai R, Thiagarajan S, Mohandas S, Natarajan K, Shanmugasekar C, Ramalingam S (2010) Haim Munk syndrome and Papillon Lefevre syndrome–allelic mutations in cathepsin C with variation in phenotype. Int J Dermatol 49:541–543.

    Article  PubMed  Google Scholar 

  13. 13.

    Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, Hashimoto I, Uitto J (2001) Papillon-Lefèvre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol 116:339–343.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Nagy N, Vályi P, Csoma Z, Sulák A, Tripolszki K, Farkas K et al (2014) CTSC and Papillon-Lefèvre syndrome: detection of recurrent mutations in Hungarian patients, a review of published variants and database update. Mol Genet Genomic Med 2:217–228.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Moghaddasian M, Arab H, Dadkhah E, Boostani H, Babak AR, Abbaszadegan MR (2014) Protein modeling of cathepsin C mutations found in Papillon-Lefèvre syndrome. Gene 538:182–187.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yang W, Xia W, Mao J, Xu D, Chen J, Feng S et al (2011) High level expression, purification and activation of human dipeptidyl peptidase I from mammalian cells. Protein Expr Purif 76:59–64.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Dağlioğlu C (2017) Cloning, expression, and activity analysis of human cathepsin C in the yeast Pichia pastoris. Turk J Biol 41:746–753.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Romero-Quintana JG, Frías-Castro LO, Arámbula-Meraz E, Aguilar-Medina M, Dueñas-Arias JE, Melchor-Soto JD et al (2013) Identification of novel mutation in cathepsin C gene causing Papillon-Lefèvre Syndrome in Mexican patients. BMC Med Genet 14:7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Yousry YM, El-Latif AEA, El-Gawad RYA (2018) Case report: clinical manifestation and dental management of Papillon-Lefèvre syndrome. F1000Res 7:1420.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Tyagi S, Thomas AM, Balla V, Kundra R (2019) Cu-sil dentures: a novel approach of Papillon-Lefèvre syndrome management. J Indian Soc Pedod Prev Dent 37:303–307.

    Article  PubMed  Google Scholar 

  21. 21.

    Millet C, Virard F, Lienhart G, Ducret M (2020) Digital prosthodontic management of a young patient with Papillon-Lefèvre syndrome: a clinical report. J Prosthet Dent 123:548–552.

    Article  PubMed  Google Scholar 

  22. 22.

    Giannetti L, Apponi R, Dello Diago AM, Jafferany M, Goldust M, Sadoughifar R (2020) Papillon-Lefèvre syndrome: oral aspects and treatment. Dermatol Ther.

    Article  PubMed  Google Scholar 

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This study was supported financially by The PSG & Sons’ Charities Trust, Coimbatore, Tamil Nadu, India.

Author information




SM and TS: Conceptualization, design of study and interpretation; SM: Laboratory experimentation and Writing—original draft preparation; BP and RR: Clinical data collection interpretations; SR, TS and RS: Writing—review and editing; SR and RS: Funding acquisition and supervision; All the authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Thiagarajan Sairam or Reena Rai or Ramalingam Sankaran.

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The authors did not declare any conflict of interest.

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This study was approved by the Institutional Human Ethics Committee (IHEC), PSG Institute of Medical Sciences and Research, Coimbatore, India and the study procedures were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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The patient and his parents gave written informed consent for genetic analysis and for a future possible publication.

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Meenu, S., Pradeep, B., Ramalingam, S. et al. Papillon–Lefèvre syndrome (PLS) with novel compound heterozygous mutation in the exclusion and Peptidase C1A domains of Cathepsin C gene. Mol Biol Rep (2020).

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  • Papillon Lefevre syndrome
  • Cathepsin C
  • Compound heterozygote
  • Missense mutation
  • Palmoplantar keratoderma.