Alternative titles; symbols
HGNC Approved Gene Symbol: NTRK2
Cytogenetic location: 9q21.33 Genomic coordinates (GRCh38): 9:84,668,522-85,027,054 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.33 | Developmental and epileptic encephalopathy 58 | 617830 | Autosomal dominant | 3 |
| Obesity, hyperphagia, and developmental delay | 613886 | Autosomal dominant | 3 |
For background information on the neurotrophic tyrosine receptor kinase (NTRK) family, see NTRK1 (191315). The NTRK family specifically interacts with neurotrophins, a small family of secreted proteins (see NGFR; 162010), and mediates their function. NTRK2, also known as TRKB, is the receptor for brain-derived neurotrophic factor (BDNF; 113505). Together NTRK2 and BDNF regulate both short-term synaptic functions and long-term potentiation of brain synapses.
Nakagawara et al. (1995) isolated cDNAs spanning the entire coding region of both human full-length and truncated forms of TRKB from human brain cDNA libraries. The full-length TRKB coded for a protein of 822 amino acid residues. The putative mature peptide sequence was 49% and 55% homologous to human NTRK1 and NTRK3 (191316), respectively. Nine of 13 cysteine residues, 4 of 12 N-glycosylation sites in the extracellular domain, and 10 of 13 tyrosine residues in the intracellular domain are conserved among NTRK1, NTRK2, and NTRK3. Two major sizes of NTRK2 transcripts were expressed in human brain.
Using bioinformatic and RT-PCR analyses, Luberg et al. (2010) determined that the NTRK2 gene is subject to a complex pattern of splicing and produces at least 36 possible protein isoforms. The full-length TRKB protein contains an N-terminal signal sequence, followed by a cysteine-rich domain, a leucine-rich domain, a second cysteine-rich domain, 2 immunoglobulin (Ig)-like domains that make up the BDNF-binding region, a transmembrane domain, an SHC (see 600560)-binding motif, a tyrosine kinase domain near the C terminus, and a C-terminal PLC-gamma (PLCG1; 172420)-docking site. Exons 6 through 15, except for exon 12, are common to all transcripts. Transcripts initiating from exon 5c, and lacking exons 1 through 5, encode an N-terminally truncated protein lacking the signal sequence, leucine-rich domain, and most of the cysteine-rich domains of full-length TRKB. PCR analysis showed that some TRKB transcripts were expressed in all tissues examined, including heart, skeletal muscle, kidney, pancreas, colon, testis, and prostate, as well as in all specific adult brain regions. Transcripts initiating from exon 5c were detected predominantly in neural tissues, although at a much lower level than those containing exon 5. PCR analysis showed that expression of specific TRKB transcripts was differentially regulated during development of human prefrontal cortex. Expression of the TRKB transcript encoding the full-length protein peaked during the toddler stage. Most epitope-tagged TRKB proteins localized to both the cell membrane and cytoplasm of transfected cells.
Soppet et al. (1991) demonstrated that the gp145 gene product of the TRKB gene is rapidly phosphorylated on tyrosine residues upon exposure to BDNF and NTF3. Furthermore, the gp145 gene product specifically binds BDNF and NTF3 but does not bind NGF. Squinto et al. (1991) found that both BDNF and NTF3, but not NGF, bind to TRKB, for which no ligand had previously been identified. Human TRKA and TRKC have been cloned and mapped to chromosome 1 and chromosome 15, respectively.
Bothwell (1996), Carter and Lewin (1997), and Bibel and Barde (2000) reviewed neurotrophins and their receptors. Nerve growth factor receptor (NGFR; 162010) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF (see 162030), but also other neurotrophins, including BDNF, neurotrophin-3 (NTF3; 162660), and neurotrophin-4 (NTF4; 162662). As a monomer, NGFR binds NGF with low affinity. Higher affinity binding is achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1), TRKB (NTRK2), and TRKC (NTRK3). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF4 and BDNF, and NTF3, respectively (Ip et al., 1993). NTF3 also binds to TRKA and TRKB, but with significantly lower affinity.
To identify metastasis-associated oncogenes, Douma et al. (2004) designed an unbiased genomewide functional screen solely on the basis of anoikis (apoptosis resulting from loss of cell-matrix interactions) suppression. The screen was based on rat intestinal epithelial cells owing to their nonmalignancy and high sensitivity to anoikis. Douma et al. (2004) reported the identification of TRKB as a potent and specific suppressor of caspase-associated anoikis of nonmalignant epithelial cells. By activating the phosphatidylinositol-3-hydroxykinase/protein kinase B pathway, TRKB induced the formation of large cellular aggregates that survived and proliferated in suspension. In mice, these cells formed rapidly growing tumors that infiltrated lymphatics and blood vessels to colonize distant organs. Consistent with the ability of TRKB to suppress anoikis, metastases--whether small vessel infiltrates or large tumor nodules--contained very few apoptotic cells. Douma et al. (2004) concluded that these observations demonstrate the potent oncogenic effects of TRKB and uncover a specific prosurvival function that may contribute to its metastatic capacity, providing a possible explanation for the aggressive nature of human tumors that overexpress TRKB.
Neurotrophins (NTFs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. To determine whether neurotrophins could influence development and maturation of the human fetal testis, Robinson et al. (2003) examined the cell-specific expression and distribution of several members of the neurotrophin family and their receptors during the second trimester, with particular emphasis on NT4 and TRKB. They detected expression of mRNA for NGF, NTF3 and NTF4 (162662), brain-derived neurotrophic factor (BDNF; 113505), the high-affinity receptors TRKA, TRKB, and TRKC, and the low-affinity p75 receptor (NGFR) in the human testis between 14 and 19 weeks' gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, NGF and NT3 were mainly expressed in Sertoli and interstitial cells. The authors concluded that these data demonstrate the expression of neurotrophins and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells.
Berghuis et al. (2005) found that anandamide, an endogenous cannabinoid, acted as a chemoattractant and regulated rat Cb1r (CNR1; 114610)-positive interneuron migration by activating Trkb. Anandamide-induced chemotaxis was additive with Bdnf-induced interneuron migration, but prolonged anandamide exposure antagonized Bdnf-induced differentiation of cortical interneurons. Neuronal differentiation was associated with simultaneous recruitment of Cb1r and Trkb to axon terminal segments in Cb1r-positive interneurons, and endocannabinoids induced the assembly of Cb1r/Trkb complexes. In utero exposure of pups to cannabinoids found in marijuana increased the density of hippocampal Cck (118440)-positive interneurons, suggesting that overactivation of CB1Rs affects postnatal positioning of developing neurons and prevents proper patterning of cortical neuronal networks.
Using engineered embryonic stem cells, Nikoletopoulou et al. (2010) demonstrated that the neurotrophin receptors TRKA (191315) and TRKC (191316) instruct developing neurons to die, both in vitro and in vivo. By contrast, TRKB, a closely related receptor primarily expression in the central nervous system, does not. These results indicated that TRKA and TRKC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic factor-dependent for survival. Nikoletopoulou et al. (2010) suggested that the expansion of the TRK gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control.
Lobo et al. (2010) showed that deletion of TrkB, the BDNF receptor, selectively from D1+ or D2+ neurons in the nucleus accumbens oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, Lobo et al. (2010) next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppressed cocaine reward, with opposite effects induced by activation of D1+ neurons.
By assaying transfected HEK293 cells, Luberg et al. (2010) showed that all TRKB isoforms tested could autophosphorylate except for TRKB-T-TK-delta-17, which lacks part of the intracellular tyrosine kinase domain. However, TRKB-T-TK-delta-17 could be phosphorylated by full-length TRKB.
Using a fluorescence resonance energy transfer-based sensor for TrkB and 2-photon fluorescence lifetime imaging microscopy, Harward et al. (2016) monitored TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to structural long-term potentiation induction, Harward et al. (2016) found fast (onset less than 1 min) and sustained (more than 20 min) activation of TrkB in the stimulated spine that depends on NMDAR (see 138249) and CaMKII (see 114078) signaling and on postsynaptically synthesized BDNF (113505). Harward et al. (2016) confirmed the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons, and showed rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines. Harward et al. (2016) demonstrated that this postsynaptic BDNF-TrkB signaling pathway is necessary for both structural and functional long-term potentiation. The authors concluded that these findings revealed a spine-autonomous, autocrine signaling mechanism involving NMDAR-CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.
Yeo et al. (2004) stated that the TRKB gene contains 24 exons.
Luberg et al. (2010) noted that NTRK2 exons 1, 2, 3, 4, and the majority of exon 5 constitute the 5-prime UTR of a number of NTRK2 transcripts. These exons are GC rich, and each can serve as transcription start sites. Luberg et al. (2010) also identified an additional NTRK2 exon, 5c, which introduces a new transcription start site 1.2 kb downstream from exon 5. Exons 5 and 9 contain translational start sites.
Slaugenhaupt et al. (1995) identified a dinucleotide repeat within a cosmid containing NTRK2 and used this marker to map the gene near D9S1 on the proximal long arm of chromosome 9. By fluorescence in situ hybridization and somatic cell hybrid mapping, Nakagawara et al. (1995) mapped the NTRK2 gene to 9q22.1. Slaugenhaupt et al. (1995) excluded NTRK2 as a candidate for familial dysautonomia.
By fluorescence in situ hybridization, Valent et al. (1997) mapped the NTRK2 to chromosome 9q22.
Gross (2018) mapped the NTRK2 gene to chromosome 9q21.33 based on an alignment of the NTRK2 sequence (GenBank AF400441) with the genomic sequence (GRCh38).
Dorsey et al. (2006) stated that mouse Ntrk2 maps to chromosome 13.
Obesity, Hyperphagia, and Developmental Delay
In a boy with early-onset obesity, hyperphagia, and severe developmental delay (OBHD; 613886), Yeo et al. (2004) identified a heterozygous de novo mutation in the TRKB gene (Y722C; 600456.0001). The authors noted phenotypic similarities between their patient and the mouse model of TrkB deficiency reported by Xu et al. (2003).
In a cohort of 40 patients with craniosynostosis in whom routine molecular testing was negative, Miller et al. (2017) performed exome sequencing and identified a girl with hyperphagic obesity, developmental delay, and left coronal synostosis who was heterozygous for a nonsense mutation in the NTRK2 gene (G444X; 600456.0002).
In an 11-year-old girl (HSJ0335), born of unrelated parents from Guatemala, with OBHD, Hamdan et al. (2017) identified a de novo heterozygous missense mutation in the NTRK2 gene (T720I; 600456.0004). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but Hamdan et al. (2017) noted that the mutation was adjacent to another mutation reported in a patient with a similar phenotype (Y722C; 600456.0001).
Developmental and Epileptic Encephalopathy 58
In 4 unrelated patients with developmental and epileptic encephalopathy-58 (DEE58; 617830), Hamdan et al. (2017) identified a de novo heterozygous missense mutation in the NTRK2 gene (Y434C; 600456.0003). The mutations were found by whole-exome or whole-genome sequencing. Functional studies of the variant were not performed, but the authors postulated a dominant-negative or gain-of-function effect. The patients were ascertained from several large cohorts of patients with seizures and developmental delay who underwent genetic studies.
Pilocytic Astrocytoma
Jones et al. (2013) described whole-genome sequencing of 96 pilocytic astrocytomas (see 137800), with matched RNA sequencing for 73 samples, conducted by the International Cancer Genome Consortium PedBrain Tumor Project. Jones et al. (2013) identified recurrent activating mutations in FGFR1 (136350) and PTPN11 (176876) and novel NTRK2 fusion genes in noncerebellar tumors. Novel BRAF (164757)-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, Jones et al. (2013) identified the same FGFR1 mutations in a subset of H3F3A (601128)-mutated pediatric glioblastoma with additional alterations in the NF1 gene (613113).
To study the function of TRKB in the cerebellum, Rico et al. (2002) deleted the Trkb gene in mouse cerebellar precursors by Wnt1-driven Cre-mediated recombination. Despite the absence of Trkb, the mature cerebellum of mutant mice appeared similar to that of wildtype, with all types of cells present in normal numbers and positions. Granule and Purkinje cell dendrites appeared normal, and the former had typical numbers of excitatory synapses. By contrast, inhibitory interneurons were strongly affected. Although present in normal number, inhibitory interneurons exhibited reduced amounts of GABAergic markers and developed reduced numbers of GABAergic boutons and synaptic specializations. Thus, Rico et al. (2002) concluded that TRKB is essential to the development of GABAergic neurons and regulates synapse formation in addition to its role in the development of axon terminals.
Using the Cre-loxP recombination system, Minichiello et al. (1999) generated conditionally gene targeted mice in which the knockout of Ntrk2 was restricted to the forebrain and occurred only during postnatal development. The conditional knockout mice were viable and developed without gross morphologic defects. In behavioral tests, the adult homozygous mutant mice exhibited a severe impairment in stressful spatial learning tasks, but succeeded in less demanding, simple learning tasks. Both the homozygous and heterozygous mutant mice showed reduced hippocampal long-term synaptic potentiation, but the heterozygotes appeared behaviorally normal. Electrophysiologic experiments led Minichiello et al. (1999) to conclude that the mutant mice had normal synaptic transmission, but impaired synaptic strengthening. The authors suggested an essential role for NTRK2 signaling in complex learning and synaptic plasticity mediated by the hippocampus and its proximally connected forebrain structures.
Minichiello et al. (2002) found that targeted disruption of the phospholipase C-gamma (PLCG; see 172420) docking site in mouse Ntrk2 impaired hippocampal long-term potentiation. Upon stimulation with BDNF, these neurons displayed impaired induction of Creb (123810) and Camk4 (114080). Targeted disruption of the SHC (see 605217) docking site had no effect on hippocampal long-term potentiation but reduced the ability of BDNF-stimulated neurons to activate mitogen-activated protein kinases (MAPKs; see 176948). Minichiello et al. (2002) concluded that MAPKs and CREB act in parallel pathways, and that NTRK2 mediates hippocampal plasticity via recruitment of PLCG and the subsequent phosphorylation of CREB and CAMK4.
The melanocortin-4 receptor (MC4R; 155541) has a critical role in regulating energy balance, and mutations in the MC4R gene result in obesity in mice and humans. Xu et al. (2003) found that similar to MC4R mutants, mouse mutants that express decreased amounts of the BDNF receptor TrkB showed hyperphagia and maturity-onset obesity, suggesting a role for BDNF in energy balance. The authors found that BDNF is an anorexigenic factor that is highly expressed in murine ventromedial hypothalamic (VMH) nuclei and is regulated by feeding status. Deficiency in MC4R signaling reduced expression of BDNF in the VMH, indicating that BDNF and its receptor TrkB are downstream components in the MC4R-mediated control of energy balance.
Zorner et al. (2003) investigated the behavioral characteristics of mice with forebrain-specific knockout of Trkb. The mice showed stereotypic hyperlocomotion with reduced explorative activity and impulsive reactions to novel stimuli. No dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis was observed under normal or stressful conditions. Zorner et al. (2003) suggested that this mouse line may be a good model of attention deficit disorder (see 143465).
Dorsey et al. (2006) noted that trisomy-16 (T16) in mouse causes altered expression of the Trkb gene on chromosome 13, with overexpression of Trkb.t1, an inactive truncated isoform of Trkb. Expression of Trkb.t1 in T16 mice is associated with defects in Bdnf responsiveness, altered phosphorylation and signaling through Trkb, elevated resting Ca(2+) levels, and accelerated neuronal cell death. These effects are rescued by overexpression of full-length, catalytically active Trkb. Using gene targeting, Dorsey et al. (2006) showed that reduction of Trkb.t1 in T16 mice to levels found in wildtype euploid mice reduced apoptotic cell death in T16 neurons in vitro and in vivo and restored T16 neuronal responses to Bdnf. Trkb.t1 upregulation in T16 mice selectively reduced Akt (see 164730) activation by Trkb in response to Bdnf, but it did not alter Trkb-mediated activation of Erk (see 176948) signaling. Dorsey et al. (2006) concluded that alternative splicing of the Trkb gene regulates Trkb activity and that Trkb.t1 inhibits Trkb activity, but not through a simple dominant-negative mechanism.
Dorfman et al. (2014) observed that oocyte-specific deletion of Ntrk2 in mice resulted in postpubertal oocyte death, loss of follicular organization, and early adulthood infertility. Oocytes lacking Ntrk2 did not respond to gonadotropins with activation of Pik3 (see 171834)/Akt-mediated signaling. In a cell line expressing both a truncated form of Ntrk2 (Ntrk2.t1) and Kiss1r (604161), Bdnf activated Ntrk2 expression only in the presence of kisspeptin (KISS1; 603286), suggesting that Bdnf and Kiss1 act in concert to mediate the effect of gonadotropins on Ntrk2 expression in oocytes. In addition, the oocytes of Ntrk2-intact mice failed to respond to gonadotropins in the absence of Kiss1r. Dorfman et al. (2014) concluded that the preovulatory gonadotropin surge promotes oocyte survival at the onset of reproductive cyclicity by inducing oocyte expression of full-length NTRK2 (NTRK2.FL) receptors that set in motion an AKT-mediated survival pathway. The authors also suggested that gonadotropins activate NTRK2.FL expression via a dual pathway involving BDNF and KISS1, produced in granulosa cells, and their respective receptors, NTRK2.T1 and KISS1R, expressed in oocytes.
Koudelka et al. (2014) found that mice with a mutation in the Shc-docking site (tyr515) of Trkb exhibited a reduction in gustatory neuron survival at both early and late stages of development, when survival is dependent on Bdnf and Nt4, respectively. Lingual innervation and taste bud morphology, which are dependent on Bdnf, were altered in these mutant mice. In contrast, mutation in the Plcg-docking site (tyr816) of Trkb did not affect gustatory neuron survival. In these mutant mice, innervation to the tongue was delayed and taste receptor function was altered. Koudelka et al. (2014) concluded that TRKB regulates expression of specific taste receptors by distinct signaling pathways.
In an 8-year-old boy with early-onset obesity, hyperphagia, and severe developmental delay (OBHD; 613886), Yeo et al. (2004) identified heterozygosity for a de novo A-to-G transition in exon 22 of the TRKB gene, resulting in a tyr722-to-cys (Y722C) substitution at a highly conserved residue in the activation loop of the catalytic domain. In vitro functional expression studies showed that the Y722C mutation was expressed normally on the cell surface, but resulted in markedly impaired ligand-induced phosphorylation, as well as impaired downstream MAPK (176948) phosphorylation.
In a 7.5-year-old girl (family 37) with obesity, hyperphagia, and developmental delay (OBHD; 613886), who also exhibited left coronal synostosis, Miller et al. (2017) identified heterozygosity for a c.1330G-T transversion in the NTRK2 gene, resulting in a gly444-to-ter (G444X) substitution with predicted loss of the entire intracellular tyrosine kinase domain. The mutation was not found in her unaffected mother; DNA was unavailable from her father.
In 4 unrelated patients with developmental and epileptic encephalopathy-58 (DEE58; 617830), Hamdan et al. (2017) identified a de novo heterozygous c.1301A-G transition (c.1301A-G, NM_006180.4) in the NTRK2 gene, resulting in a tyr434-to-cys (Y434C) substitution at the beginning of the transmembrane domain. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function or dominant-negative effect. The patients had onset of seizures in the first days to months of life.
In an 11-year-old girl (HSJ0335), born of unrelated parents from Guatemala, with obesity, hyperphagia, and developmental delay (OBHD; 613886), Hamdan et al. (2017) identified a de novo heterozygous c.2159C-T transition (c.2159C-T, NM_006180.4) in the NTRK2 gene, resulting in a thr720-to-ile (T720I) substitution in the catalytic domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but Hamdan et al. (2017) noted that the mutation was adjacent to another mutation reported in a patient with a similar phenotype (Y722C; 600456.0001). Y722C had previously been shown to result in markedly impaired ligand-induced phosphorylation, as well as impaired downstream MAPK (176948) phosphorylation.
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