Novel 9 amino acid in‐frame deletion in the <i><scp>NTRK1</scp></i> tyrosine kinase domain in a patient with congenital insensitivity to pain with anhydrosis

Amin, S.; Forrester, Natalie; Norman, A.W.; Lux, Alison; Vijayakumar, K. R.

doi:10.1111/cge.13064

Cited by 6 publications

(4 citation statements)

References 3 publications

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“…They are also produced as a result of the increasingly employed CRISPR/CAS9 technology for genome editing [15]. Indels which are multiples of three nucleotides will maintain the open reading frame of genes but result in shorter/longer amino acid strands potentially altering the structure and function of proteins [16]. Indels which are not a multiple of three nucleotides give rise to frameshift mutations, thereby coding for an entirely different set of amino acids or resulting in a premature stop codon [17].…”

Section: Introductionmentioning

confidence: 99%

Derived Polymorphic Amplified Cleaved Sequence (dPACS): A Novel PCR-RFLP Procedure for Detecting Known Single Nucleotide and Deletion–Insertion Polymorphisms

Kaundun

Marchegiani

Hutchings

et al. 2019

IJMS

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Most methods developed for detecting known single nucleotide polymorphisms (SNP) and deletion–insertion polymorphisms (DIP) are dependent on sequence conservation around the SNP/DIP and are therefore not suitable for application to heterogeneous organisms. Here we describe a novel, versatile and simple PCR-RFLP procedure baptised ‘derived Polymorphic Amplified Cleaved Sequence’ (dPACS) for genotyping individual samples. The notable advantage of the method is that it employs a pair of primers that cover the entire fragment to be amplified except for one or few diagnostic bases around the SNP/DIP being investigated. As such, it provides greater opportunities to introduce mismatches in one or both of the 35–55 bp primers for creating a restriction site that unambiguously differentiates wild from mutant sequences following PCR-RFLP and horizontal MetaPhorTM gel electrophoresis. Selection of effective restriction enzymes and primers is aided by the newly developed dPACS 1.0 software. The highly transferable dPACS procedure is exemplified here with the positive detection (in up to 24 grass and broadleaf species tested) of wild type proline106 of 5-enolpyruvylshikimate-3-phosphate synthase and its serine, threonine and alanine variants that confer resistance to glyphosate, and serine264 and isoleucine2041 which are key target-site determinants for weed sensitivities to some photosystem II and acetyl-CoA carboxylase inhibiting herbicides, respectively.

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Section: Introductionmentioning

confidence: 99%

Derived Polymorphic Amplified Cleaved Sequence (dPACS): A Novel PCR-RFLP Procedure for Detecting Known Single Nucleotide and Deletion–Insertion Polymorphisms

Kaundun

Marchegiani

Hutchings

et al. 2019

IJMS

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“…However, there is no clear correlation between the genotype and phenotype of CIPA patients (2,19). Among 128 different mutations, we found that only four reports about gross deletion mutations (2,(20)(21)(22)(23); the largest deletion range was about 1,403 bp, which included exon5-6 (Supplementary Table 3). It affects the extracellular domain (2).…”

Section: Discussionmentioning

confidence: 96%

Novel Gross Deletion Mutations in NTRK1 Gene Associated With Congenital Insensitivity to Pain With Anhidrosis

Chen

Tang

et al. 2021

Front. Pediatr.

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Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis, recurrent fever, and intellectual disability. CIPA is mainly caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). This study aims to identify pathogenic mutations underlying CIPA in two unrelated Chinese families.Methods: DNA was extracted from blood samples of patients and their available family members and subjected to whole exome sequencing (WES). Real-time PCR (qPCR), Gap-PCR, and Sanger sequencing were applied to verify the identified variants.Result: We found novel compound gross deletion mutations [exon1-6 del (g.1-1258_10169del); exon5-7 del (g.6995_11999del)] of NTRK1 (MIM 191315) gene in family 1 and the compound heterozygous mutations [c.851-33T>A; exon5-7 del (g.6995_11999del)] in family 2. Interestingly, we discovered the intragenic novel gross deletion [exon5-7 del (g.6995_11999del)] mediated by recombination between Alu elements.Conclusions: The present study highlights two rare gross deletion mutations in the NTRK1 gene associated with CIPA in two unrelated Chinese families. The deletion of exon1-6 (g.1-1258_10169del) is thought to be the largest NTRK1 deletion reported to date. Our findings expand the mutation spectrum of NTRK1 mutations in the Chinese and could be useful for prenatal interventions and more precise pharmacological treatments to patients. WES conducted in our study is a convenient and useful tool for clinical diagnosis of CIPA and other associated disorders.

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“…Patients with CIPA have mutations in NTRK1, the gene encoding TrkA, that affect TrkA expression and/or activity. Because mutations are found widely throughout the gene, symptoms vary from severe to mild and may include mental retardation, self-mutilation, multiple fractures, and developmental delay (14)(15)(16)(17)(18)(19). Few studies have biochemically characterized the mutations found in CIPA (19).…”

Section: Introductionmentioning

confidence: 99%

“…CIPA is a rare autosomal recessive disease characterized by loss of algesia and an inability to sweat. The worldwide incidence of CIPA is about 1 in 125,000,000 ( 14 , 15 ). Patients with CIPA have mutations in NTRK1 , the gene encoding TrkA, that affect TrkA expression and/or activity.…”

Section: Introductionmentioning

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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Novel 9 amino acid in‐frame deletion in the NTRK1 tyrosine kinase domain in a patient with congenital insensitivity to pain with anhydrosis

Abstract: Schematic presentation of NTRK1 protein structure. Variants identified in this study are shown in red and previously reported variants associated with CIPA are shown in black (LRM, leucine rich motif; Ig, immunoglobulin-like domain; TM, transmembrane domain; TK, tyrosine kinase domain).

Cited by 6 publications

References 3 publications

Derived Polymorphic Amplified Cleaved Sequence (dPACS): A Novel PCR-RFLP Procedure for Detecting Known Single Nucleotide and Deletion–Insertion Polymorphisms

Derived Polymorphic Amplified Cleaved Sequence (dPACS): A Novel PCR-RFLP Procedure for Detecting Known Single Nucleotide and Deletion–Insertion Polymorphisms

Novel Gross Deletion Mutations in NTRK1 Gene Associated With Congenital Insensitivity to Pain With Anhidrosis

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

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