Corresponding author:
Arab H.R
Professor of Periodontics
Department of Periodontics and Implant Dentistry
Mashhad University of Medical Sciences
Mashhad, Iran postal code: 9177948988
Telefax: +985138829501-15
arabHR@mums.ac.ir
Abstract
Background: PLS is a rare autosomal recessive disorder characterized by the palmar-plantar hyperkeratosis and severe degeneration of the periodontium. The defects in cathepsin C gene, are responsible for PLS. In this study, we analyzed the whole exomes of CTSC gene in a family with history of PLS.
Methods: Genomic DNA was extracted from peripheral blood and genotype analysis was performed. The mutated protein sequence was used to find the best possible tertiary structure for homology modeling. The homology modeling of the novel mutation was then performed using the online Swiss-Prot server. The results were also analyzed for to verify its validity.
Results: The analysis of CTSC gene elucidated a novel insertion GAC. The novel mutation was proved by analyzing 50 healthy control volunteers. Modeling of the novel found mutation in CTSC gene revealed structural defects that may have caused the functional abnormalities.
Discussion: The structural analysis of the mutated protein model identifies changes in the stereo-chemical and the energy level of the mutated protein. Since this protein play a role in the activation of granule serine proteases from cytotoxic T lymphocytes, natural killer cells, mast cells, such structural defects may lead to its malfunction causing dysfunctioning of immune defense mechanisms.
Keywords
Papillon–Lefevre syndrome- Cathepsin C mutation- Palmoplantar hyperkeratosis- Energy minimization -Tertiary structure
Introduction
Papillon–Lefevre syndrome (PLS; OMIM245000) is a rare inherited autosomal recessive disorder firstly reported by French physicians Papillon and Lefevre in 1924. According to the latest reports, the prevalence of this syndrome is 1-4 in a million people with equal distribution in males and females(Cury et al., 2002; R J Gorlin, Sedano, & Anderson, 1964; Basapogu Sreeramulu, Shyam, Ajay, & Suman, 2015). Although, a variety of studies has recently reported different affected Iranian families with PLS, there is not any accurate incidence of PLS in Iranian families(Arnold, Bordoli, Kopp, & Schwede, 2006; Farjadian, Kiyanimanesh, Abbaszadegan, & Lotfazar, 2007; Farjadian, Lotfazar, & Ghaderi, 2008; Moghaddasian et al., 2014). The clinical symptoms of the syndrome is normally revealed in the first four years of patient life (It may be already present in the first 3 months of life however generally the palmoplantar hyperkeratosis and the severe periodontitis present simultaneously between 1 and 4 ages)(Farkas et al., 2013; Papillon, 1924; B Sreeramulu, Haragopal, Shalini, Sudha, & Kiran, 2012). This disorder is characterized by a symmetrical palmar-plantar hyperkeratosis - dry scaly patches on the palms and the soles’s skin- and severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium)(Robert J Gorlin, 2000). Usually, complete deciduous tooth loss occurs before the 6 years of birth and then, the periodontitis disappears until all permanent teeth are fully grown out. All permanent teeth are normally lost when the patients turn 15 years old(Robert J Gorlin, Cohen Jr, & Hennekam, 2001; Wu et al., 2016).
Other symptoms of PLS are hyperhidrosis, intracranial calcification, arachnodactyly, increased susceptibility to infections, hearing loss, mental retardation, oculocutaneous albinism, bent nail syndrome, corneal cell hyperkeratosis, acanthosis nigricans, thicker cutaneous granular layer, etc(Almuneef, Al Khenaizan, Al Ajaji, & Al-Anazi, 2003; Borroni et al., 1985; Farkas et al., 2013; Haneke, 1979; Khandpur & Reddy, 2001; Oğuzkurt, Tanyel, Büyükpamukçu, & Hiçsönmez, 1996; Basapogu Sreeramulu et al., 2015; Tosti, Manuzzi, Bardazzi, & Costa, 1988; Wani, Devkar, Patole, & Shouche, 2006; Wu et al., 2016). Furthermore, this disorder may also be accompanied with other symptoms such as the skin, liver, kidneys and brain abscesses(R J Gorlin et al., 1964; Kanthimathinathan et al., 2013; Mercy, Singh, Ghorpade, Das, & Upadhyay, 2013; Morgan, Hannon, & Lakhoo, 2011).
Susceptibility to bacterial infections (often in respiratory tract) is approximately increased in 20-25% of patients with recurrent pyogenic infections as a result of decreased neutrophil, lymphocyte or monocyte functions in PLS patients(6,12). The quality of patient’s life can be improved by medications for hyperkeratosis and periodontal care. However, periodontal management of PLS is still a big challenge for treatment(Lundgren, Crossner, Twetman, & Ullbro, 1996; Lundgren & Renvert, 2004; Tekin et al., 2016).
The cathepsin C (CTSC) gene is mapped on chromosome 11q14.2 and encodes a cysteine-lysosomal protease called cathepsin C. Mutations in this gene, are responsible for Papillon–Lefevre syndrome(Hart et al., 1999; Toomes et al., 1999). Now, 91 CTSC mutations have been reported in PLS patients(http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CTSC , n.d.; Pallos et al., 2010). Approximately more than half of these mutations are missense; however, a broad spectrum of mutation types have been described(Tekin et al., 2016).
Recently it has been revealed that Loss of function in lysosomal protease cathepsin C is the main genetic cause of the disease. This tetrameric protein plays a critical role in the removal of dipeptides from free N-terminal of some hormones (including gastrin, glucagon and angiotensin II) and the activation of granule serine proteases from cytotoxic T lymphocytes, natural killer cells (granzymes A and B), mast cells (tryptase and chymase) and neutrophils (cathepsin G and elastase)(de Haar et al., 2004; Idon, Olasoji, & Fusami, 2015; Romero-Quintana et al., 2013; Toomes et al., 1999).
Since 1999, several mutations have been reported in the CTSC gene majorly related to PLS. Herein, we present the case of a 6-year-old boy affected by insertion GAC (p.122ins.T) in the third exon of the CTSC gene.
Material and Methods