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

2021 ◽  
Vol 9 ◽  
Author(s):  
Lulu Li ◽  
Chao Jia ◽  
Yue Tang ◽  
Yuanyuan Kong ◽  
Yaofang Xia ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Recurrent Fever ◽  
Tyrosine Kinase Receptor ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Alu Elements ◽  
Deletion Mutations ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

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.

scholarly journals Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis

2017 ◽  
Vol 45 (2) ◽  
pp. 549-555 ◽  
Author(s):  
Ting Wang ◽  
Haibo Li ◽  
Jingjing Xiang ◽  
Bin Wei ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nonsense Mutation ◽  
Mutation Screening ◽  
Receptor Type ◽  
Tyrosine Kinase Receptor ◽  
Site Mutation ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron–exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

scholarly journals A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

2018 ◽  
Vol 23 (3) ◽  
pp. 202-206 ◽  
Author(s):  
Margherita Marchi ◽  
Vincenzo Provitera ◽  
Maria Nolano ◽  
Marcello Romano ◽  
Simona Maccora ◽  
...  
Keyword(s):  
Compound Heterozygous ◽  
Splicing Mutation ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

scholarly journals Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations

2010 ◽  
Vol 31 (9) ◽  
pp. E1670-E1686 ◽  
Author(s):  
James J. Cox ◽  
Jony Sheynin ◽  
Zamir Shorer ◽  
Frank Reimann ◽  
Adeline K. Nicholas ◽  
...  
Keyword(s):  
Deletion Mutations ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Novel SCN9A Mutations in a Compound Heterozygous Girl with Congenital Insensitivity to Pain

2020 ◽  
Author(s):  
Bas Stunnenberg ◽  
Charlotte Haaxma ◽  
Mieke van Haelst ◽  
Maria Ponson-Wever ◽  
Eline Verberne ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Frameshift Mutation ◽  
Rare Disorder ◽  
Compound Heterozygous ◽  
Α Subunit ◽  
Voltage Gated ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain ◽  
Inactivating Mutations

AbstractCongenital Insensitivity to Pain (CIP) is a rare disorder that is characterized by the inability to perceive pain. It is caused by bi-allelic inactivating mutations in the SCN9A gene, which encodes the pore-forming α-subunit of the nerve voltage-gated sodium channel (Nav1.7). Patients with CIP are unable to feel pain from noxious stimuli, including heat, but all other peripheral somatosensory modalities function normally. Often anosmia is present as an additional feature. We report a patient with CIP caused by compound heterozygous SCN9A mutations: a novel in-frame deletion of exon 7 and a novel frameshift mutation. The identification of these mutations expands the spectrum of mutations associated with CIP.

scholarly journals Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Kai Yang ◽  
Yi-Cheng Xu ◽  
Hua-Ying Hu ◽  
Ya-Zhou Li ◽  
Qian Li ◽  
...  
Keyword(s):  
Mrna Level ◽  
Sensory Neuropathy ◽  
Functional Study ◽  
Structure Stability ◽  
Compound Heterozygous ◽  
The Novel ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.

scholarly journals Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis

2019 ◽  
Author(s):  
Andrés López-Cortés ◽  
Ana Karina Zambrano ◽  
Patricia Guevara-Ramírez ◽  
Byron Albuja Echeverría ◽  
Santiago Guerrero ◽  
...  
Keyword(s):  
Native American ◽  
High Altitude ◽  
African Ancestry ◽  
Genomic Analysis ◽  
European Ancestry ◽  
Tyrosine Kinase Receptor ◽  
Pain Matrix ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

ABSTRACTCongenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

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