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