TY - JOUR
T1 - Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain
AU - Kantaputra, Piranit
AU - Daroontum, Teerada
AU - Kitiyamas, Kantapong
AU - Piyakhunakorn, Panat
AU - Kawasaki, Katsushige
AU - Sathienkijkanchai, Achara
AU - Wasant, Pornswan
AU - Vatanavicharn, Nithiwat
AU - Yasanga, Thippawan
AU - Kaewgahya, Massupa
AU - Tongsima, Sissades
AU - Cox, Timothy C.
AU - Arold, Stefan T.
AU - Ohazama, Atsushi
AU - Ngamphiw, Chumpol
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
KW - absence of pain sensation
KW - acro-osteolysis
KW - corneal scar
KW - dental anomalies
KW - lack of pain sensation
KW - Plec mutation
KW - tooth agenesis
UR - http://www.scopus.com/inward/record.url?scp=85197318478&partnerID=8YFLogxK
U2 - 10.3390/ijms25126358
DO - 10.3390/ijms25126358
M3 - Article
C2 - 38928066
AN - SCOPUS:85197318478
SN - 1661-6596
VL - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 12
M1 - 6358
ER -