Alternative titles; symbols
HGNC Approved Gene Symbol: NGF
SNOMEDCT: 128206006;
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:115,285,917-115,338,249 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | Neuropathy, hereditary sensory and autonomic, type V | 608654 | Autosomal recessive | 3 |
Nerve growth factor is a polypeptide involved in the regulation of growth and differentiation of sympathetic and certain sensory neurons (review by Levi-Montalcini, 1987).
Ullrich et al. (1983) showed that the nucleotide sequence of human and mouse beta-NGF are very similar. Mouse Ngf consists of 3 types of subunits, alpha, beta and gamma, which specifically interact to form a 7S, 130,000-Da complex. This complex contains 2 identical 118-amino acid beta-chains, which are solely responsible for nerve growth stimulating activity of NGF. Human DNA fragments coding for NGF were identified by Zabel et al. (1984) using a mouse submaxillary cDNA probe.
The arrest of dorsal root axonal regeneration at the transitional zone between the peripheral and central nervous system has been repeatedly described. Ramer et al. (2000) demonstrated that with trophic support to damaged sensory axons, this regenerative barrier is surmountable. In adult rats with injured dorsal roots, treatment with NGF, neurotrophin-3 (NT3; 162660), or glial cell line-derived neurotrophic factor (GDNF; 600837), but not brain-derived neurotrophic factor (BDNF; 113505), resulted in selective regrowth of damaged axons across the dorsal root entry zone and into the spinal cord. Dorsal horn neurons were found to be synaptically driven by peripheral nerve stimulation in rats treated with NGF, NT3, and GDNF, demonstrating functional reconnection. In behavioral studies, rats treated with NGF and GDNF recovered sensitivity to noxious heat and pressure. Ramer et al. (2000) concluded that neurotrophic factor treatment may serve as a viable treatment in promoting recovery from root avulsion injuries.
Sanico et al. (2000) used RT-PCR, Western blot analysis, and ELISA to evaluate NGF expression and release in subjects with or without allergic rhinitis. They found that subjects with allergic rhinitis had significantly decreased NGF mRNA in superficial nasal scrapings and significantly higher baseline concentrations of NGF protein in nasal lavage fluids compared with control subjects. Nasal provocation with allergen significantly increased NGF protein in nasal lavage fluids of subjects with allergic rhinitis but not of control subjects. Sanico et al. (2000) concluded that their data provide evidence of a steady state of dysregulation in mucosal NGF expression and release in allergic rhinitis and support a role of this neurotrophin in the pathophysiology of allergic inflammatory disease of the human airways.
Chuang et al. (2001) demonstrated that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1 (602076), a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5,bisphosphate levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma (172420) to TRK-alpha (TRKA) (NTRK1; 191315) is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggested that VR1 associates with this complex. Chuang et al. (2001) concluded that their studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signaling systems regulates other members of the TRP channel family.
Although proneurotrophins have been considered inactive precursors, Lee et al. (2001) demonstrated that the proforms of NGF and the proforms of BDNF are secreted and cleaved extracellularly by the serine protease plasmin (173350) and by selective matrix metalloproteinases (MMP7, 178990; MMP3, 185250). ProNGF is a high-affinity ligand for p75(NTR) (NGFR; 162010), and induced p75(NTR)-dependent apoptosis in cultured neurons with minimal activation of TRK-alpha-mediated differentiation or survival. The biologic action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75(NTR) to mediate apoptosis and mature forms activating TRK receptors to promote survival.
MacInnis and Campenot (2002) demonstrated that application of nerve growth factor covalently cross-linked to beads increased the phosphorylation of TRKA and AKT (164730), but not of mitogen-activated protein kinase (MAPK1; 176948), in cultured rat sympathetic neurons. NGF beads or iodine-125-labeled NGF beads supplied to distal axons resulted in the survival of over 80% of the neurons for 30 hours, with little or no retrograde transport of iodine-125-labeled NGF. Application of free iodine-125-labeled NGF produced 20-fold more retrograde transport, but only 29% of the neurons survived. Thus, MacInnis and Campenot (2002) concluded that a neuronal survival signal can reach the cell bodies unaccompanied by the NGF that initiated it.
Nykjaer et al. (2004) demonstrated that proNGF creates a signaling complex by simultaneously binding to p75(NTR) and sortilin (602458). Sortilin acts as a coreceptor and molecular switch governing the p75(NTR)-mediated proapoptotic signal induced by proNGF. Together with p75(NTR), sortilin facilitates the formation of a composite high-affinity binding site for proNGF. Thus, sortilin serves as a coreceptor and molecular switch, enabling neurons expressing TRK and p75(NTR) to respond to a proneurotrophin and to initiate proapoptotic rather than prosurvival actions. In the absence of sortilin, regulated activity of extracellular proteases may cleave proNGF to mature NGF, promoting TRK-mediated survival signals. Nykjaer et al. (2004) concluded that NGF-induced neuronal survival and death is far more complicated than previously appreciated, as it depends on an intricate balance between proNGF and mature NGF, as well as on the spatial and temporal expression of 3 distinct receptors: TRKA, p75(NTR), and sortilin.
Harrington et al. (2004) reported that after brain injury in rats and mice, the unprocessed precursor of NGF (proNGF) was induced and secreted in an active form capable of triggering apoptosis in culture. They further demonstrated that proNGF binds the neurotrophin receptor p75 in vivo and that disruption of this binding results in complete rescue of injured adult corticospinal neurons. These data suggested that proNGF binding to p75 is responsible for the death of adult corticospinal neurons after brain injury.
In a study of regulators of nerve growth factor, Ieda et al. (2004) found that endothelin-1 (EDN1; 131240) specifically upregulated NGFB expression in primary cultured cardiomyocytes. EDN1-induced NGF augmentation was mediated by EDNRA (131243), Gi-beta-gamma (see 139310), PKC (see 176960), the Src family (see 190090), EGFR (131550), MAPK3 (601795), MAPK14 (600289), AP1 (165160), and CEBPD (116898). Either conditioned medium or coculture with EDN1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. Edn1-deficient mice exhibited reduced NGF expression and norepinephrine concentration in the heart, reduced cardiac sympathetic innervation, excess apoptosis of sympathetic stellate ganglia, and loss of neurons at the late embryonic stage. Cardiac-specific overexpression of NGF in Edn1-deficient mice overcame the reduced sympathetic expression and loss of stellate ganglia neurons. Ieda et al. (2004) concluded that EDN1 plays a critical role in sympathetic innervation of the heart.
Kuruvilla et al. (2004) found that the related neurotrophins NGF and NT3 (162660), acting through a common receptor, TRKA (191315), were required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supported TRKA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT3 could not. Final target-derived NGF promoted expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT3. Kuruvilla et al. (2004) proposed that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TRKA internalization, trafficking, and retrograde axonal signaling.
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, NT3 and NT4 (162662), BDNF (113505), the high-affinity receptors TRKA, TRKB (600456), and TRKC (191316), and the low-affinity p75 receptor (NGFR; 162010) 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. Robinson et al. (2003) 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.
Deppmann et al. (2008) reported that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived NGF promoted expression of its own receptor TrkA (191315) in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor (BDNF; 113505) and neurotrophin-4 (162662), which, through the receptor p75 (162010), can kill neighboring neurons with low retrograde NGF-TrkA signaling, whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. Deppmann et al. (2008) suggested that 3 target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects.
Hepburn et al. (2014) found that stimulation of macrophages with Staphylococcus aureus, but not with other bacteria or staphylococcal species, resulted in secretion of both pro-NGF and mature NGFB, but not other neurotrophins. Secretion was mediated by activation of NLRP3 (606416) and NLRC4 (606831). S. aureus strains that triggered lower levels of NGFB, possibly due to differences in both host and bacterial proteases, were associated with increased all-cause mortality. Macrophages, neutrophils, and TRKA-transfected HeLa cells responded to NGFB with sustained calcium signaling. Cells expressing a TRKA mutant (G517E; 191315.0015) associated with hereditary sensory and autonomic neuropathy IV (HSAN4; 256800) had reduced calcium signaling, whereas activation of wildtype TRKA led to enhanced phagocytosis, proinflammatory cytokine release, phagosomal superoxide generation, and destruction of S. aureus. Studies in zebrafish suggested that NGFB-TRKA signaling is an evolutionarily conserved component of vertebrate immunity to S. aureus. Hepburn et al. (2014) concluded that cystine-knot proteins, such as NGFB, have an evolutionarily conserved dual function in both nerve development and antistaphylococcal immunity, possibly explaining aberrant nerve growth following soft-tissue infection by S. aureus.
In somatic cell hybrid studies, Zabel et al. (1984) found that the human HindIII DNA fragments for NGF, as demonstrated in Southern blots, cosegregated with chromosome 1. Using a cell line with a 1;2 translocation, they narrowed the assignment to 1pter-p21. This is the same area as that implicated cytogenetically in neuroblastoma (1pter-p32) and the segment containing a neuroblastoma-related RAS oncogene.
Using fragments of a cloned human gene for the beta subunit of nerve growth factor as hybridization probes in somatic cell hybrid studies, Francke et al. (1983) mapped the NGFB locus to 1p22. Oncogene NRAS (164790) maps to the same band. Both nerve growth factor and epidermal growth factor (131530) are on mouse chromosome 3; in man they are on different chromosomes (Zabel et al., 1985). Both factors are present in unusually high levels in male mouse submaxillary glands and both show similarities in temporal activation during development and androgen regulation. There is no known structural homology between them, however. Arguing from comparative mapping data, Zabel et al. (1985) suggested that the NGFB locus is localized in the p22.1 to distal p21 region of chromosome 1. The distal part of human 1p shows conserved homology with mouse chromosome 4. The region of homology includes the genes ENO1 (172430), PGD (172200), GDH (138090), AK2 (103020), and PGM1 (171900). The conserved segment extends to PGM1 (homologous to mouse Pgm2), which is localized to human 1p22.1. From about 1p22.1 toward the centromere, there is a region of homology to mouse chromosome 3. This region contains AMY1 and AMY2 in mouse and man and NGF in the mouse. AMY is mapped to human 1p21. Using a method for improved resolution of in situ hybridization, Middleton-Price et al. (1987) concluded that NGFB is located within band 1p13. This explains the apparently anomalous linkage data between NGFB and PGM1, both of which had previously been assigned to 1p22.1 but showed no positive linkage. Garson et al. (1987) confirmed the assignment of NGFB to 1p13. The confusion has, however, not been completely dispelled. According to Dracopoli (1988), NGFB is telomeric to TSHB (188540). The 2 loci are in the same 100-kb PFGE fragment, show virtually no recombination (lod = 43 at theta = 0.0), and are antithetically regulated by thyroid hormone (Dracopoli et al., 1988), yet TSHB has been mapped to 1p22. Dracopoli and Meisler (1990) concluded from linkage analysis and pulsed field gel electrophoresis that TSHB, NGFB, and NRAS form a tightly linked gene cluster located in the same chromosomal band. Their location proximal to the AMY2B gene in 1p21 and close linkage to the alpha-satellite centromeric repeat D1Z5 provided strong evidence that the correct assignment for these 3 loci is 1p13 and not 1p22. By fluorescence in situ hybridization, Mitchell et al. (1995) mapped NGFB to 1p13.1.
Carrier et al. (1996) constructed a 3-Mb YAC contig, including the NGFB gene. They found that the gene order of this region of the short arm of chromosome 1 was cen--CD2(186990)--CD58(153420)--ATP1A1 (182310)--NGF--TSHB--NRAS--tel.
Crystal Structure
He and Garcia (2004) determined the 2.4-angstrom crystal structure of the prototypic neurotrophin, NGF, complexed with the extracellular domain of p75. The complex is composed of an NGF homodimer asymmetrically bound to a single p75. The p75 protein binds along the homodimeric interface of NGF, which disables NGF's symmetry-related second p75 binding site through an allosteric conformational change. He and Garcia (2004) concluded that neurotrophin signaling through p75 may occur by disassembly of p75 dimers and assembly of asymmetric 2:1 neurotrophin/p75 complexes, which could potentially engage a Trk receptor to form a trimolecular signaling complex.
Einarsdottir et al. (2004) described a large family from northern Sweden in which affected members exhibited loss of deep pain and temperature perception. Because severe reduction of unmyelinated nerve fibers and moderate loss of thin myelinated nerve fibers were also observed in these patients, they best fit into the category of hereditary sensory and autonomic neuropathy type V (HSAN5; 608654). In contrast to HSAN4 (256800), mental abilities and most other neurologic responses remained intact. Using a model of recessive inheritance, the authors identified an 8.3-Mb region on chromosome 1p13.2-p11.2 shared by the affected individuals. Analysis of candidate disease genes revealed a mutation in the coding region of the NGFB gene that cosegregated with the disease phenotype (162030.0001). This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions (such as mental abilities) from those involved in peripheral pain pathways.
Carvalho et al. (2011) identified a homozygous loss of function mutation in the NGFB gene (162030.0002) in a consanguineous Emirati Bedouin family with HSAN5 and mild mental retardation. The findings expanded the phenotype of HSAN5 to be closer to that of HSAN4, indicating that there is a phenotypic spectrum due to changes in the NGF/TRKA signaling pathway. In a reevaluation of the family reported by Carvalho et al. (2011), Hepburn et al. (2014) noted that patients with HSAN5 also had frequent severe Staphylococcus aureus infections of the skin, teeth, joints, and bone, suggesting a pathogen-specific immune defect.
Abnormality of NGF had been suspected, with some supporting evidence, in familial dysautonomia (223900) and in 2 forms of neurofibromatosis (101000, 162200). The use of the 'candidate gene' approach to mapping disease and determining its cause is illustrated by the work of Breakefield et al. (1984). Using a cloned genomic probe for human beta-NGF, they identified RFLPs in the beta-NGF gene, and in 4 informative families with 2 children with familial dysautonomia found 'no consistent co-inheritance of specific alleles with the disease.' Thus, they appear to have excluded a defect in or near the structural gene for beta-NGF as the cause of familial dysautonomia. Using 2 RFLPs related to the beta-NGF gene, Darby et al. (1985) could exclude this gene as the site of the mutation in 4 families with neurofibromatosis of the classic type (162200).
In a large consanguineous family from northern Sweden with loss of deep pain and temperature perception (HSAN5; 608654), Einarsdottir et al. (2004) demonstrated that 3 severely affected family members were homozygous for a 661C-T transition in the NGFB gene. The mutation was predicted to result in a substitution of tryptophan for arginine-211 (R211W), corresponding to position 100 in the mature protein, in a highly conserved region of the protein.
By in vitro functional expression studies in rat pheochromocytoma cells Carvalho et al. (2011) showed that the mutant protein was unable to activate the TRKA receptor (NTRK1; 191315). However, a small amount of residual mutant protein was secreted, suggesting that it may act as a hypomorphic allele.
In 6 sibs from a consanguineous Emirati Bedouin family with HSAN5 (608654), Carvalho et al. (2011) identified a homozygous 680C-A transversion and a 2-bp deletion (681delGG) in exon 1 of the NGFB gene (referred to as CAdGG), resulting in a frameshift and replacement of the terminal 15 amino acids with a novel 43-amino acid terminal sequence. The mutation creates additional cysteine residues in the novel C terminus, potentially able to compete in disulfide bond formation. In vitro functional expression studies in rat pheochromocytoma cells showed that the mutant protein was unable to activate the TRKA receptor (NTRK1; 191315), consistent with a loss of function. The mutant protein was not secreted, suggesting impaired processing. In addition to inability to feel pain, all patients had mild mental retardation, thus expanding the phenotypic spectrum of HSAN5. In a reevaluation of the family reported by Carvalho et al. (2011), Hepburn et al. (2014) noted that patients with HSAN5 also had frequent severe Staphylococcus aureus infections of the skin, teeth, joints, and bone, suggesting a pathogen-specific immune defect.
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