The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis

Chelsee Hewitt, Derek McCormick, Gerry Linden, Dusan Turk, Igor Stern, Ian Wallace, Louise Southern, Liqun Zhang, Rebecca Howard, Pedro Bullon, Melanie Wong, Richard Widmer, Khaled Abdul Gaffar, Lama Awawdeh, Jim Briggs, Reza Yaghmai, Ethlin W. Jabs, Peter Hoeger, Oliver Bleck, Stefan G. RüdigerGregor Petersilka, Maurizio Battino, Peter Brett, Faiez Hattab, Mohamed Al-Hamed, Philip Sloan, Carmel Toomes, Mike Dixon, Jacqueline James, Andrew P. Read, Nalin Thakker

Research output: Contribution to journalArticle

Abstract

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T > A/p. V129E, c.935A > G/p.Q312R, and c.1235A > G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 ± SD 576.8 μ moles/mg/min vs. 1,678.7 ± SD 527.2 μ moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS.

Original languageEnglish (US)
Pages (from-to)222-228
Number of pages7
JournalHuman Mutation
Volume23
Issue number3
DOIs
StatePublished - 2004

Fingerprint

Cathepsin C
Aggressive Periodontitis
Genes
Mutation
Palmoplantar Keratoderma
Skin Manifestations
Haplotypes

Keywords

  • Cathepsin C
  • CTSC
  • Papillon-Lefèvre syndrome
  • Periodontitis
  • PLS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hewitt, C., McCormick, D., Linden, G., Turk, D., Stern, I., Wallace, I., ... Thakker, N. (2004). The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis. Human Mutation, 23(3), 222-228. https://doi.org/10.1002/humu.10314

The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis. / Hewitt, Chelsee; McCormick, Derek; Linden, Gerry; Turk, Dusan; Stern, Igor; Wallace, Ian; Southern, Louise; Zhang, Liqun; Howard, Rebecca; Bullon, Pedro; Wong, Melanie; Widmer, Richard; Gaffar, Khaled Abdul; Awawdeh, Lama; Briggs, Jim; Yaghmai, Reza; Jabs, Ethlin W.; Hoeger, Peter; Bleck, Oliver; Rüdiger, Stefan G.; Petersilka, Gregor; Battino, Maurizio; Brett, Peter; Hattab, Faiez; Al-Hamed, Mohamed; Sloan, Philip; Toomes, Carmel; Dixon, Mike; James, Jacqueline; Read, Andrew P.; Thakker, Nalin.

In: Human Mutation, Vol. 23, No. 3, 2004, p. 222-228.

Research output: Contribution to journalArticle

Hewitt, C, McCormick, D, Linden, G, Turk, D, Stern, I, Wallace, I, Southern, L, Zhang, L, Howard, R, Bullon, P, Wong, M, Widmer, R, Gaffar, KA, Awawdeh, L, Briggs, J, Yaghmai, R, Jabs, EW, Hoeger, P, Bleck, O, Rüdiger, SG, Petersilka, G, Battino, M, Brett, P, Hattab, F, Al-Hamed, M, Sloan, P, Toomes, C, Dixon, M, James, J, Read, AP & Thakker, N 2004, 'The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis', Human Mutation, vol. 23, no. 3, pp. 222-228. https://doi.org/10.1002/humu.10314
Hewitt, Chelsee ; McCormick, Derek ; Linden, Gerry ; Turk, Dusan ; Stern, Igor ; Wallace, Ian ; Southern, Louise ; Zhang, Liqun ; Howard, Rebecca ; Bullon, Pedro ; Wong, Melanie ; Widmer, Richard ; Gaffar, Khaled Abdul ; Awawdeh, Lama ; Briggs, Jim ; Yaghmai, Reza ; Jabs, Ethlin W. ; Hoeger, Peter ; Bleck, Oliver ; Rüdiger, Stefan G. ; Petersilka, Gregor ; Battino, Maurizio ; Brett, Peter ; Hattab, Faiez ; Al-Hamed, Mohamed ; Sloan, Philip ; Toomes, Carmel ; Dixon, Mike ; James, Jacqueline ; Read, Andrew P. ; Thakker, Nalin. / The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis. In: Human Mutation. 2004 ; Vol. 23, No. 3. pp. 222-228.
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AU - Hewitt, Chelsee

AU - McCormick, Derek

AU - Linden, Gerry

AU - Turk, Dusan

AU - Stern, Igor

AU - Wallace, Ian

AU - Southern, Louise

AU - Zhang, Liqun

AU - Howard, Rebecca

AU - Bullon, Pedro

AU - Wong, Melanie

AU - Widmer, Richard

AU - Gaffar, Khaled Abdul

AU - Awawdeh, Lama

AU - Briggs, Jim

AU - Yaghmai, Reza

AU - Jabs, Ethlin W.

AU - Hoeger, Peter

AU - Bleck, Oliver

AU - Rüdiger, Stefan G.

AU - Petersilka, Gregor

AU - Battino, Maurizio

AU - Brett, Peter

AU - Hattab, Faiez

AU - Al-Hamed, Mohamed

AU - Sloan, Philip

AU - Toomes, Carmel

AU - Dixon, Mike

AU - James, Jacqueline

AU - Read, Andrew P.

AU - Thakker, Nalin

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