{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:49Z","timestamp":1760144989107,"version":"build-2065373602"},"reference-count":106,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T00:00:00Z","timestamp":1717804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chiang Mai University"},{"name":"Genomics Thailand Grant by the Health System Research Institute of Thailand"},{"name":"Office of Sponsored Research (OSR)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C&gt;T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans.<\/jats:p>","DOI":"10.3390\/ijms25126358","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T10:08:43Z","timestamp":1718014123000},"page":"6358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-0881","authenticated-orcid":false,"given":"Piranit","family":"Kantaputra","sequence":"first","affiliation":[{"name":"Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-218X","authenticated-orcid":false,"given":"Teerada","family":"Daroontum","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kantapong","family":"Kitiyamas","sequence":"additional","affiliation":[{"name":"Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panat","family":"Piyakhunakorn","sequence":"additional","affiliation":[{"name":"Panare Hospital, Dental Public Health Division, Panare District, Surat Thani 94130, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushige","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 950-2181, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achara","family":"Sathienkijkanchai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pornswan","family":"Wasant","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-8070","authenticated-orcid":false,"given":"Nithiwat","family":"Vatanavicharn","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thippawan","family":"Yasanga","sequence":"additional","affiliation":[{"name":"Medical Science Research Equipment Center, Research Administration Section, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massupa","family":"Kaewgahya","sequence":"additional","affiliation":[{"name":"Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sissades","family":"Tongsima","sequence":"additional","affiliation":[{"name":"National Biobank of Thailand, National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-5528","authenticated-orcid":false,"given":"Timothy C.","family":"Cox","sequence":"additional","affiliation":[{"name":"Departments of Oral & Craniofacial Sciences, School of Dentistry, and Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5278-0668","authenticated-orcid":false,"given":"Stefan T.","family":"Arold","sequence":"additional","affiliation":[{"name":"Biological and Environmental Science and Engineering Division, Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Ohazama","sequence":"additional","affiliation":[{"name":"Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 950-2181, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-397X","authenticated-orcid":false,"given":"Chumpol","family":"Ngamphiw","sequence":"additional","affiliation":[{"name":"National Biobank of Thailand, National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Deng, L., and Chiu, I.M. 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