title: Protein modeling of cathepsin C mutations found in Papillon-Lefèvre syndrome.
abstract: BACKGROUND
  Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by hyperkeratosis involving the palms, soles, elbows, and knees followed by periodontitis, destruction of alveolar bone, and loss of primary and permanent teeth. Mutations of the lysosomal protease cathepsin C gene (CTSC) have been shown to be the genetic cause of PLS. This study analyzed CTSC mutations in five Iranian families with PLS and modeled the protein for mutations found in two of them.
  
  
  METHODS
  DNA analysis was performed by direct automated sequencing of genomic DNA amplified from exonic regions and associated splice intron site junctions of CTSC. RFLP analyses were performed to investigate the presence of previously unidentified mutation(s) in control groups. Protein homology modeling of the deduced novel mutations (P35 delL and R272P) was performed using the online Swiss-Prot server for automated modeling and analyzed and tested with special bioinformatics tools to better understand the structural effects caused by mutations in cathepsin C protein (CTSC).
  
  
  RESULTS
  Six Iranian patients with PLS experienced premature tooth loss and palm plantar hyperkeratosis. Sequence analysis of CTSC revealed a novel mutation (P35delL) in exon 1 of Patient 1, and four previously reported mutations; R210X in Patient 2, R272P in Patient 3, Q312R in two siblings of family 4 (Patients 4 and 5), and CS043636 in Patient 6. RFLP analyses revealed different restriction fragment patterns between 50 healthy controls and patients for the P35delL mutation. Modeling of the mutations found in CTSC, P35delL in Patient 1 and R272P in Patient 3 revealed structural effects, which caused the functional abnormalities of the mutated proteins.
  
  
  CONCLUSIONS
  The presence of this mutation in these patients provides evidence for founder CTSC mutations in PLS. This newly identified P35delL mutation leads to the loss of a leucine residue in the protein. The result of this study indicates that the phenotypes observed in these two patients are likely due to CTSC mutations. Also, structural analyses of the altered proteins identified changes in energy and stereochemistry that likely alter protein function.
authors.affiliation: Human Genetics Division, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran; Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran.
authors.forename: Morteza
authors.initials: M
authors.lastname: Moghaddasian
authors.affiliation: Dental Research Center, School of Dentistry, MUMS, Mashhad, Iran.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Arab
authors.affiliation: Human Genetics Division, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran; School of Systems Biology, George Mason University, Manassass, VA, USA.
authors.forename: Ezzat
authors.initials: E
authors.lastname: Dadkhah
authors.affiliation: Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Boostani
authors.affiliation: Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran.
authors.forename: Azam Rezaei
authors.initials: AR
authors.lastname: Babak
authors.affiliation: Human Genetics Division, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran; Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran. Electronic address: abbaszadeganmr@mums.ac.ir.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Abbaszadegan
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D020789:Cathepsin C / Q000737:chemistry / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010214:Papillon-Lefevre Disease / Q000175:diagnosis / Q000235:genetics*; D011487:Protein Conformation; D055815:Young Adult
chemical_list: C533918:CTSC protein, human; D020789:Cathepsin C
keywords: Cathepsin C mutation; Energy minimization; Palmoplantar hyperkeratosis; Papillon–Lefèvre syndrome; Pre-pubertal periodontitis; Tertiary structure