Alternative titles; symbols
HGNC Approved Gene Symbol: NTF4
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,058,284-49,065,035 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Glaucoma 1, open angle, 1O | 613100 | 3 |
Differentiation, survival, and function of neurons in vertebrates are controlled by multiple, target-derived neurotrophic factors. The best characterized mammalian neurotrophic factors are 4 structurally related 13- to 14-kD basic proteins known as neurotrophins (Berkemeier et al., 1992).
For background information on neurotrophins and their receptors, see NGFR (162010).
Using sequences specific to a neurotrophin identified in Xenopus and viper and designated neurotrophin-4, Ip et al. (1992) isolated a neurotrophin from both human and rat genomic DNAs that appears to represent the mammalian counterpart. Mammalian NT4 had many unusual features compared to the previously identified neurotrophins and was less conserved evolutionarily than the others; however, mammalian NT4 displayed bioactivity and TRK receptor specificity similar to that of Xenopus NT4.
Pasutto et al. (2009) examined the postmortem retina of a patient with no history of eye disease and used in situ hybridization to confirm a specific NTF4 signal localized to the ganglion cell layer of the retina.
Berkemeier et al. (1992) identified a cluster of genes on human chromosome 19 that includes neurotrophin-5 (NT5) and 3 pseudogenes, designated NTF6A, NTF6B, and NTF6G. The NTF5 and NTF6 gene loci were mapped to chromosome 19 by Southern analysis of somatic cell hybrid panels. In the mouse, the Ntf5 gene was assigned to chromosome 7.
Ip et al. (1992) mapped the human NTF4 gene and NTF4 pseudogene to chromosome 19q13.3 by FISH.
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 (600456). They detected expression of mRNA for nerve growth factor (NGF; 162030, 162030), NTF3 (162660) and NTF4, brain-derived neurotrophic factor (BDNF; 113505), the high-affinity receptors TRKA (191315), TRKB, 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. 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.
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 in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of BDNF and NT4, which, through the receptor p75, 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.
In a 3-stage study, Pasutto et al. (2009) analyzed the NTF4 gene in a total of 892 patients with high- and normal-tension primary open-angle glaucoma (GLC1O; 613100) and 895 controls, and identified 6 different heterozygous missense mutations in 15 (1.7%) patients (see, e.g., 162662.0001-162662.0003). A heterozygous missense mutation was also identified in 1 population-based control who had not been ophthalmologically examined (p less than 0.0002). On the basis of molecular modeling, all NT4 variants were predicted to affect either dimer stability or the interaction between the NT4 dimer and its receptor TRKB. Pasutto et al. (2009) concluded that there was strong genetic evidence that NTF4 variants are associated with primary open-angle glaucoma.
Liu et al. (2010) analyzed the NTF4 gene in 443 POAG cases and 533 controls of European ancestry from the southeastern United States, and identified nonsynonymous coding changes in 5 cases and 12 controls, including 2 variants previously identified by Pasutto et al. (2009) (A88V, 162662.0001; R206W, 162662.0002). In addition, Liu et al. (2010) identified a heterozygous nonsense mutation (S29X) in the NTF4 gene in a 56-year-old control with hyperopia and presbyopia. Liu et al. (2010) concluded that heterozygous coding changes in NTF4 do not play a significant role in the pathogenesis of POAG in this population. In response, Pasutto and Reis (2010) noted that the control group used by Liu et al. (2010) was significantly younger than theirs (mean age, 64.7 years vs 73.9 years, respectively). Pasutto and Reis (2010) stated, however, that they could not exclude the possibility that some of the variants identified in the original study or this one are benign variants. They concluded that a metaanalysis of different studies in glaucoma patients with population-based controls would be required to clarify the role of NTF4 in glaucoma.
Neurotrophin-4 (NTF4 or NT4) has been also referred to as neurotrophin-5 (NTF5 or NT5). Ibanez (1996) noted that confusion over the nomenclature of this factor arose because this mammalian neurotrophin is much more divergent from its amphibian counterpart (NT4) than are the other members of the family; hence the designation 'neurotrophin-5.' Subsequent studies demonstrated a functional correspondence between this protein and the amphibian NT4 protein. Some laboratories adopted the nomenclature 'neurotrophin-4/5' to denote the mammalian counterpart of Xenopus NT4.
Xie et al. (2000) examined the learning and memory of Ntf4 -/- mice by using fear conditioning. In both cue and context conditioning, they found significant deficits in the Ntf4 mutants at 2 and 24 hours after training but not at 30 minutes. Hippocampal slices from the mutant mice showed normal basal synaptic transmission, short-term plasticity, and decremental long-term potentiation. These findings, together with the normal short-term memory, suggested that the hippocampal development of Ntf4 -/- mice was largely unaffected. However, consistent with the long-term memory defects, the long-lasting long-term potentiation at the same synapses was attenuated significantly in the mutant mice. The results were interpreted as suggesting that NTF4 plays a physiologic role essential for hippocampus- and amygdala-dependent long-term memory and that NTF4 may be useful in the therapy of acquired disorders of learning and memory.
This variant, formerly titled GLAUCOMA 1, OPEN ANGLE, O, has been reclassified based on the report of Lek et al. (2016).
In 5 patients with primary open-angle glaucoma (GLC1O; 613100), 1 with elevated intraocular pressure and 4 with normal pressure, Pasutto et al. (2009) identified heterozygosity for a mutation in the NTF4 gene, resulting in an ala88-to-val (A88V) substitution at a conserved residue in the NGF domain.
Liu et al. (2010) analyzed the NTF4 gene in 443 POAG cases and 533 controls of European ancestry from the southeastern United States, and identified the A88V variant in 1 patient and 5 controls. They concluded that NTF4 variants are not associated with an elevated risk of POAG in this population.
Lek et al. (2016) found the A88V variant in homozygosity in 8 individuals in the ExAC database and noted that it had a high allele frequency (0.0215) in the South Asian population, suggesting that it is not pathogenic.
In 5 patients with primary open-angle glaucoma (GLC1O; 613100), 3 with elevated intraocular pressure and 2 with normal pressure, Pasutto et al. (2009) identified heterozygosity for a mutation in the NTF4 gene, resulting in an arg206-to-trp (R206W) substitution at a conserved residue in the NGF domain. In vitro analysis demonstrated impaired ligand-mediated TRKB signaling and reduced neurite outgrowth with the R206W mutant compared to wildtype NT4.
Liu et al. (2010) analyzed the NTF4 gene in 443 POAG cases and 533 controls of European ancestry from the southeastern United States, and identified the R206W variant in 1 patient and 2 controls. They concluded that NTF4 variants are not associated with an elevated risk of POAG in this population.
In a patient with primary open-angle glaucoma (GLC1O; 613100) associated with elevated intraocular pressure, Pasutto et al. (2009) identified heterozygosity for a mutation in the NTF4 gene, resulting in an arg206-to-gln (R206Q) substitution at a conserved residue in the NGF domain.
Berkemeier, L. R., Ozcelik, T., Francke, U., Rosenthal, A. Human chromosome 19 contains the neurotrophin-5 gene locus and three related genes that may encode novel acidic neurotrophins. Somat. Cell Molec. Genet. 18: 233-245, 1992. [PubMed: 1496419] [Full Text: https://doi.org/10.1007/BF01233860]
Deppmann, C. D., Mihalas, S., Sharma, N., Lonze, B. E., Niebur, E., Ginty, D. D. A model for neuronal competition during development. Science 320: 369-373, 2008. [PubMed: 18323418] [Full Text: https://doi.org/10.1126/science.1152677]
Ibanez, C. F. Neurotrophin-4: the odd one out in the neurotrophin family. Neurochem. Res. 21: 787-793, 1996. [PubMed: 8873083] [Full Text: https://doi.org/10.1007/BF02532301]
Ip, N. Y., Ibanez, C. F., Nye, S. H., McClain, J., Jones, P. F., Gies, D. R., Belluscio, L., Le Beau, M. M., Espinosa, R., III, Squinto, S. P., Persson, H., Yancopoulos, G. D. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc. Nat. Acad. Sci. 89: 3060-3064, 1992. [PubMed: 1313578] [Full Text: https://doi.org/10.1073/pnas.89.7.3060]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
Liu, Y., Liu, W., Crooks, K., Schmidt, S., Allingham, R. R., Hauser, M. A. No evidence of association of heterozygous NTF4 mutations in patients with primary open-angle glaucoma. (Letter) Am. J. Hum. Genet. 86: 498-499, 2010. [PubMed: 20215012] [Full Text: https://doi.org/10.1016/j.ajhg.2009.11.018]
Pasutto, F., Matsumoto, T., Mardin, C. Y., Sticht, H., Brandstatter, J. H., Michels-Rautenstrauss, K., Weisschuh, N., Gramer, E., Ramdas, W. D., van Koolwijk, L. M. E., Klaver, C. C. W., Vingerling, J. R., Weber, B. H. F., Kruse, F. E., Rautenstrauss, B., Barde, Y.-A., Reis, A. Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma. Am. J. Hum. Genet. 85: 447-456, 2009. [PubMed: 19765683] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.016]
Pasutto, F., Reis, A. Response to Liu et al. (Letter) Am. J. Hum. Genet. 86: 500 only, 2010.
Robinson, L. L. L., Townsend, J., Anderson, R. A. The human fetal testis is a site of expression of neurotrophins and their receptors: regulation of the germ cell and peritubular cell population. J. Clin. Endocr. Metab. 88: 3943-3951, 2003. [PubMed: 12915691] [Full Text: https://doi.org/10.1210/jc.2003-030196]
Xie, C.-W., Sayah, D., Chen, Q.-S., Wei, W.-Z., Smith, D., Liu, X. Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proc. Nat. Acad. Sci. 97: 8116-8121, 2000. [PubMed: 10869436] [Full Text: https://doi.org/10.1073/pnas.140204597]