Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain
Issued Date
2024-06-01
Resource Type
ISSN
16616596
eISSN
14220067
Scopus ID
2-s2.0-85197318478
Journal Title
International Journal of Molecular Sciences
Volume
25
Issue
12
Rights Holder(s)
SCOPUS
Bibliographic Citation
International Journal of Molecular Sciences Vol.25 No.12 (2024)
Suggested Citation
Kantaputra P., Daroontum T., Kitiyamas K., Piyakhunakorn P., Kawasaki K., Sathienkijkanchai A., Wasant P., Vatanavicharn N., Yasanga T., Kaewgahya M., Tongsima S., Cox T.C., Arold S.T., Ohazama A., Ngamphiw C. Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain. International Journal of Molecular Sciences Vol.25 No.12 (2024). doi:10.3390/ijms25126358 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/99581
Title
Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain
Author's Affiliation
Siriraj Hospital
Niigata University, Graduate School of Medical and Dental Science
King Abdullah University of Science and Technology
Faculty of Medicine, Chiang Mai University
UMKC School of Medicine
Thailand National Center for Genetic Engineering and Biotechnology
Chiang Mai University
Panare Hospital
Niigata University, Graduate School of Medical and Dental Science
King Abdullah University of Science and Technology
Faculty of Medicine, Chiang Mai University
UMKC School of Medicine
Thailand National Center for Genetic Engineering and Biotechnology
Chiang Mai University
Panare Hospital
Corresponding Author(s)
Other Contributor(s)
Abstract
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>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.