Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies.
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior, and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon. An NTRK1 autophosphorylation assay showed that c.1786G>A (p.Asp596Asn) abolished autophosphorylation of NTRK1. In addition, Western blotting showed that c.704C>G (p.Ser235*) and c.2350_2363del (p.Leu784Serfs*79) blunted NTRK1 expression to undetectable levels. The four novel NTRK1 mutations we report here will expand the repertoire of NTRK1 mutations in CIPA patients, and further our understanding of CIPA pathogenesis.
Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.|Department of Neurology, Chonnam National University Hwasun Hospital, Hwasun, Jeonnam, Republic of Korea.
Tai-Seung
TS
Nam
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
Wenting
W
Li
Department of Pharmacology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Somy
S
Yoon
Department of Pharmacology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Gwang Hyeon
GH
Eom
Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Myeong-Kyu
MK
Kim
Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Republic of Korea.
Sung Taek
ST
Jung
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
Seok-Yong
0000-0001-7193-292X
SY
Choi
D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D004558:Electric Stimulation; D005192:Family Health; D005260:Female; D057809:HEK293 Cells; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics*; D014162:Transfection; D055815:Young Adult
D020917:Receptor, trkA
CIPA; HSAN-IV; NTRK1; TRKA; congenital insensitivity to pain with anhidrosis