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NTRK1
neurotrophic receptor tyrosine kinase 1
The NTRK1 gene provides instructions for a protein vital to the development and survival of nerve cells, particularly those involved in transmitting pain, temperature, and touch sensations. The NTRK1 gene encodes the neurotrophic receptor tyrosine kinase 1 protein, which is essential for the proper functioning of sensory neurons.
NTRK1 is located on the long (q) arm of chromosome 1, at band 1q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The NTRK1 gene, also known as neurotrophic receptor tyrosine kinase 1, plays a critical role in the human nervous system. It produces a protein fundamental for the growth and sustained health of nerve cells, especially those conveying sensory information such as pain, temperature, and touch. This protein is located on the surface of cells, where it functions as an enzyme.
Dysfunction in the NTRK1 protein, often due to genetic changes, can disrupt these essential processes, leading to severe neurological conditions. Understanding the NTRK1 gene's role is crucial for comprehending the mechanisms behind disorders affecting sensation and nerve development.
What the gene does
The protein encoded by the NTRK1 gene functions as a kinase, an enzyme that modifies other proteins by adding a phosphate group, a process known as phosphorylation. This action changes the activity of target proteins, enabling signal transmission within the cell. The NTRK1 protein becomes active when nerve growth factor beta (NGFβ) binds to it, triggering the NTRK1 protein to phosphorylate itself, a process called autophosphorylation.
Once activated, NTRK1 subsequently phosphorylates various other proteins. This signal transduction is necessary for transmitting signals related to cell proliferation and survival. This signalling cascade is particularly significant in sensory neurons, where it ensures their proper development and maintenance. The ability of NTRK1 to mediate these signals is fundamental for sensing pain and temperature.
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Chromosome location
The NTRK1 gene is found on chromosome 1 at position 1q23.1. This specific region on the long arm (q) of chromosome 1 is where the genetic instructions for the neurotrophic receptor tyrosine kinase 1 protein are situated. The gene's precise location on the chromosome aids in understanding its genetic context and potential interactions with neighbouring genetic material.
Protein structure
The NTRK1 protein is composed of 796 amino acids and features several distinct functional regions. The extracellular portion includes two Leucine Rich Repeats (LRR) - LRR 1 (amino acids 90-113) and LRR 2 (amino acids 116-137) - and an LRR C-terminal (LRRCT) domain (amino acids 148-193). Following these are two Ig-like C2-type domains: Ig-like C2-type 1 (amino acids 194-283) and Ig-like C2-type 2 (amino acids 299-365).
Within the intracellular part, a key region for protein interaction, specifically with SQSTM1, is located at amino acids 469-490. The catalytic activity of the protein resides within the Protein kinase domain (amino acids 510-781), which contains two critical DXXLL motifs at amino acids 537-541 and 607-611, essential for its kinase function.
Key variants
Variants within the NTRK1 gene can impact its function, potentially leading to altered protein activity or expression. These genetic changes can range from small alterations in the DNA sequence to larger structural rearrangements. The specific effect of a variant often depends on its location within the gene and how it influences the NTRK1 protein's ability to participate in nerve cell signalling and development.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.112del | p.Asp38fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.1710_1738del | p.Gln570fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.1729_1730dup | p.Val578fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.1729G>A | p.Gly577Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.1875del | p.Gln626fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.2104dup | p.Arg702fs | Pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.2140G>A | p.Gly714Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.268_277del | p.Gly89_Leu90insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.391_392del | p.Ser131fs | Pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
c.945_949del | p.Trp315fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary insensitivity to pain with anhidrosis |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the NTRK1 gene are primarily associated with inherited conditions affecting nerve function, most notably Congenital insensitivity to pain with anhidrosis (CIPA). This condition is characterised by an inability to feel pain and a reduced or absent ability to sweat. Many NTRK1 gene variants implicated in CIPA disrupt the protein's normal function, affecting crucial signalling pathways for nerve growth and survival. Additionally, somatic mutations in NTRK1 have been identified in certain cancers, such as papillary thyroid carcinoma, where they are present only in specific cells and acquired during an individual's lifetime.
UK clinical status
The NTRK1 gene is recognised within the UK's NHS Genomic Medicine Service due to its association with several conditions. It is listed on multiple 'green' panels in PanelApp, indicating strong evidence for its involvement in these disorders. These panels include DDG2P, Familial dysautonomia, Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), Intellectual disability, and Pain syndromes. This inclusion highlights the gene's clinical significance for diagnosis and genetic counselling in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the NTRK1 gene?
The NTRK1 gene provides instructions for making a protein essential for the development and survival of nerve cells, particularly sensory neurons that transmit pain, temperature, and touch sensations.
Which condition is most commonly associated with NTRK1 gene variants?
The condition most commonly associated with variants in the NTRK1 gene is Congenital insensitivity to pain with anhidrosis (CIPA), which results in an inability to feel pain and reduced sweating.
How does the NTRK1 protein contribute to nerve cell function?
The NTRK1 protein acts as a kinase, an enzyme that phosphorylates other proteins to transmit signals for cell growth and survival. It is activated by nerve growth factor beta, which is crucial for the proper functioning of sensory neurons.
References
- Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Molecular and cellular endocrinology. 2010. PMID: 19883730
- Verpoorten N, De Jonghe P, Timmerman V. Disease mechanisms in hereditary sensory and autonomic neuropathies. Neurobiology of disease. 2006. PMID: 16183296
- Pierotti MA, Greco A. Oncogenic rearrangements of the NTRK1/NGF receptor. Cancer letters. 2006. PMID: 16242838
- Miranda C, Di Virgilio M, Selleri S. Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. The Journal of biological chemistry. 2002. PMID: 11719521
- Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Human mutation. 2001. PMID: 11748840
- Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Current opinion in neurobiology. 2000. PMID: 10851172
- Indo Y, Tsuruta M, Hayashida Y. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nature genetics. 1996. PMID: 8696348