DO: 1067;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.33 | Glaucoma 1, open angle, 1O | 613100 | 3 | NTF4 | 162662 |
A number sign (#) is used with this entry because of evidence that primary open angle glaucoma-1O is caused by heterozygous mutation in the NTF4 gene (162662) on chromosome 19q13.
For a phenotypic description and a discussion of genetic heterogeneity of primary open angle glaucoma (POAG), see 137760.
In a 3-stage study, Pasutto et al. (2009) analyzed the NTF4 gene (162662) in a total of 892 patients with high- and normal-tension primary open angle glaucoma (POAG) and 895 controls, and identified 6 different heterozygous missense mutations in 15 (1.7%) patients (see, e.g., 162662.0001-162662.0003). The discovery group, which involved patients who were negative for 4 known glaucoma-associated genes, included 9 mutation-positive individuals, all of whom were sporadic cases with deceased parents and no other affected family members to date, thus precluding segregation analysis. A heterozygous missense mutation was also identified in 1 population-based control from the second replication group, who had not been ophthalmologically examined (p less than 0.0002). On the basis of molecular modeling, all NTF4 variants were predicted to affect either dimer stability or the interaction between the NTF4 dimer and its receptor TRKB (600456). The authors concluded that there was strong genetic evidence that NTF4 variants are associated with POAG.
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) (see A88V, 162662.0001, and 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.
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.