Morteza Moghaddasian1, Hamidreza Arab2, Ezzat Dadkhah3, Hamidreza Boostani4, Azam Rezaei Babak4, Mohammad Reza Abbaszadegan5. 1. 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. 2. Dental Research Center, School of Dentistry, MUMS, Mashhad, Iran. 3. 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. 4. Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran. 5. 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.
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.
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: Marcel Hanisch; Thomas Hoffmann; Lauren Bohner; Lale Hanisch; Korbinian Benz; Johannes Kleinheinz; Jochen Jackowski Journal: Int J Environ Res Public Health Date: 2019-03-09 Impact factor: 3.390
Authors: Alia M Albalawi; Jamil A Hashmi; Fatima Alfadhli; Ahmad Almatrafi; Khushnooda Ramzan; Sulman Basit Journal: Ann Dermatol Date: 2019-12-27 Impact factor: 1.444