GeneBe

NTRK1

protein-coding

neurotrophic receptor tyrosine kinase 1, the group of Immunoglobulin like domain containing|Receptor tyrosine kinases

Gene summary

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002529.4

Inheritance

AR, AD

ClinVar variants

P:209U:442B:524

Top phenotype

Insensitivity to pain, congenital, with anhidrosis

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr1:156,815,636-156,881,850

External References & Databases

Ensembl (ENSG00000198400)NCBI Gene (4914)OMIM (191315)HGNC:8031GenCCUniProt (P04629)AlphaFoldClinVar (NTRK1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~66.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary sensory and autonomic neuropathy type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: Orphanet

hereditary sensory and autonomic neuropathy type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: Labcorp Genetics (formerly Invitae)

hereditary sensory and autonomic neuropathy type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: Natera

familial medullary thyroid carcinomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007958

Submitter: Orphanet

hereditary sensory and autonomic neuropathy type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: G2P

hereditary sensory and autonomic neuropathy type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: PanelApp Australia

hereditary sensory and autonomic neuropathy type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009746

Submitter: ClinGen

In the context of congenital insensitivity to pain (CIP), the gene NTRK1 was first discovered in mice, in which homozygous knock-out led to loss of temperature and pain perception, autonomic disturbances such as alacrimation, and severe ulcerations (PMID: 8145823). In patients with the same phenotype, including anosmia, and an autosomal recessive mode of inheritance, NTRK1 was first described in 1996 (PMID: 8696348), followed by the discovery of several missense (e.g. PMID: 11159935​), stop (e.g. PMID: 28328124), frame-shift (e.g. PMID: 28328124​), and splice variants (e.g. PMID: 10330344), all falling into the biallelic loss-of-function cluster. NTRK1 is a nerve growth factor (NGF) receptor and tyrosine kinase. Following internalization, it is involved in several processes, including regulation of inflammatory factor release​ and phagocytosis. One of its substrates is TRPV1, a nonselective cation channel expressed in small nerve endings that is responsible for the perception of heat pain and that can be sensitized by the presence of NGF (PMID: 27732851). Several patient cases and animal models reproduce the highly specific CIP phenotype. In summary, NTRK1 is DEFINITIVELY associated with autosomal recessive congenital insensitivity to pain (CIP). This was repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Insensitivity to pain, congenital, with anhidrosisAR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Neurologic

Intervention: Allergy/Immunology/Infectious; Dermatologic; Neurologic

Rationale: Individuals may manifest with poor thermoregulation due to anhidrosis, which may result in potentially severe fevers, and awareness can allow measures to help control temperature in order to decrease potential sequelae; Congenital insensitivity to pain can result in injuries, some of which may in theory be preventable with early diagnosis and preventive measures (eg, tooth extraction may be indicated); Recurrent infections have been described, and preventive measures and awareness allowing early diagnosis and aggressive treatmentment of infections may be beneficial

Refs: 8696348; 10088743; 10861667; 11744315; 12949319; 15534759; 15695606; 16490492; 19618435; 20301726; 19089473; 17915006; 20647579; 21559108; 21708027; 22032467; 22355435; 22653642; 22814739; 22957891; 23112235Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NTRK1 variants in ClinVar

16 Conditions Cataloged
Hereditary insensitivity to pain with anhidrosisTotal: 1361
not providedTotal: 217
Inborn genetic diseasesTotal: 216
not specifiedTotal: 95
NTRK1-related disorderTotal: 88
Charcot-Marie-Tooth diseaseTotal: 30
Familial medullary thyroid carcinomaTotal: 14
Hereditary cancerTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002529.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
1
clinvar
13
clinvar
450
clinvar
8
clinvar
 473
missense
8
clinvar
33
clinvar
415
clinvar
62
clinvar
4
clinvar
 522
nonsense
29
clinvar
10
clinvar
4
clinvar
 43
start loss
2
clinvar
2
clinvar
 4
frameshift
53
clinvar
31
clinvar
7
clinvar
 91
splice donor/acceptor (+/-2bp)
12
clinvar
27
clinvar
3
clinvar
 42
Total105104442512121175

Highest pathogenic variant AF is 0.000016090002

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002529.4RefSeqNP_002520.217MANE Select
ENST00000524377.7EnsemblENSP00000431418.117MANE Select
NM_001007792.1RefSeqNP_001007793.117Standard
NM_001012331.2RefSeqNP_001012331.116Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
  • Neurotrophin signaling pathway - Homo sapiens (human)
  • Central carbon metabolism in cancer - Homo sapiens (human)
  • Ras signaling pathway - Homo sapiens (human)

Biological Process

  • activation of MAPKK activity
  • positive regulation of protein phosphorylation
  • protein phosphorylation
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • nervous system development

Molecular Function

  • protein tyrosine kinase activity
  • transmembrane receptor protein tyrosine kinase activity
  • GPI-linked ephrin receptor activity
  • neurotrophin receptor activity
  • neurotrophin p75 receptor binding

Cellular Component

  • Golgi membrane
  • early endosome
  • late endosome
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000524377
Coding exons
17
Length
66211
Individuals with no LoFs
125706
Homozygous LoFs
0
Heterozygous LoFs
42
Defined
125748
p
0.000167
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.034194830.8680.00003165085
Missense (PolyPhen)138194.190.710632028
Synonymous0.03962112120.9970.00001451660
Loss of Function3.191637.00.4330.00000176394

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00012rare
Latino/Admixed American0.000140.00014rare
Ashkenazi Jewish00.0absent
East Asian0.000710.00071rare
Finnish0.0000710.000046rare
European (Non-Finnish)0.000170.00017rare
South Asian0.0000330.000033rare
Other0.000170.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1850821, PubMed:1849459, PubMed:1281417, PubMed:8325889, PubMed:15488758, PubMed:17196528, PubMed:27445338). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. {ECO:0000250|UniProtKB:P35739, ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:1849459, ECO:0000269|PubMed:1850821, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.;
Disease
DISEASE: Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, ECO:0000269|PubMed:11159935, ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:18077166, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:28177573, ECO:0000269|PubMed:28328124, ECO:0000269|PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241). {ECO:0000269|PubMed:1532241, ECO:0000269|PubMed:2869410, ECO:0000269|PubMed:7565764}.;

Recessive Scores

pRec
0.689

Intolerance Scores

LoFtool
0.0395
RVIS EVS
-0.06
RVIS percentile EVS
48.91

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.697

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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