Identification of a novel mutation of the NTRK1 gene in patients with congenital insensitivity to pain with anhidrosis (CIPA)

Wang, Wenbo; Cao, Yongsong; Lyu, Shanshan; Zuo, Rongtai; Zhang, Zhen‐Lin; Kang, Qinglin

doi:10.1016/j.gene.2018.09.009

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…in the NTRK1 gene, and both of his parents were carriers for c.851‐33T>A (p.?). This variant was previously reported as pathogenic according to the ACMG classification, which led to aberrant splicing (Wang et al., 2018). Patient 2 showed compound heterozygous pathogenic variants, c.851‐33T>A (p.?)…”

Section: Resultsmentioning

confidence: 86%

“…Genotype–phenotype correlation studies show heterogeneity, while some groups report no correlation (Indo, 2002; Mardy et al., 1999), some groups identify association based on molecular structure and function of the NTRK1 gene. Patients with homozygous p.Met581Val variants, for instance, may exhibit normal body temperature and attenuated phenotypes (Miranda, Selleri, et al., 2002; Wang et al., 2018; Yotsumoto et al., 1999).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature

Cho,

Hwang,

Kwak

et al. 2024

Molec Gen & Gen Med

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BackgroundCongenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss‐of‐function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self‐mutilating behavior, and intellectual disability.MethodsClinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing.ResultsCIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3–8 years). Two patients exhibited self‐mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851‐33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574‐156_850+1113del (exons 5‐7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851‐33T>A (p.?) mutations and compound heterozygous for c.851‐33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574‐156_850+1113del (exons 5‐7 del) displayed a late onset and milder clinical manifestation.ConclusionAll three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

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Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature

Cho,

Hwang,

Kwak

et al. 2024

Molec Gen & Gen Med

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“…S2 and table S1). One of these mutations c.851-33T>A, was previously estimated to be found in heterozygosis in 1 of 968 healthy Chinese patients ( 22 ). The T>A transversion is at a splice branch site, reported to cause aberrant splicing of intron 7 in vitro, leading to a 137–base pair fragment insertion followed by a stop codon, resulting in a truncated protein.…”

Section: Resultsmentioning

confidence: 99%

Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target

et al. 2022

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Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.

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“…Variants in NTRK1 , which encodes neurotrophic receptor tyrosine kinase 1, disrupt its role in neuronal cell maintenance, thereby leading to congenital insensitivity to pain with anhidrosis. 1 , 12 , 13 , 45 , 58 , 60 , 61 , 75 , 82 , 86 , 88 , 98 , 124 , 134 , 141 , 147 , 148 , 154 NGF encodes nerve growth factor beta, the binding partner of NTRK1. Its variants lead to HSAN, type V. 14 , 37 HSAN subtypes VII and VIII were characterised more recently, and their genetic causes have been determined to be variants in SCN11A 80 , 113 , 152 and PRDM12 , 15 respectively.…”

Section: Resultsmentioning

confidence: 99%

Genetic studies of human neuropathic pain conditions: a review

Zorina-Lichtenwalter

Parisien²,

Diatchenko³

2017

Pain

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Identification of a novel mutation of the NTRK1 gene in patients with congenital insensitivity to pain with anhidrosis (CIPA)

Cited by 16 publications

References 34 publications

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature

Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target

Genetic studies of human neuropathic pain conditions: a review

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