THE PREVALENCE AND SPECTRUM OF CYP1B1 AND LTBP2 VARIANTS IN PRIMARY CONGENITAL GLAUCOMA PATIENTS OF PAKISTANI POPULATION, A SYSTEMATIC REVIEW
DOI:
https://doi.org/10.64013/bbasrjlifess.v2026i1.59Keywords:
Primary Congenital Glaucoma (PCG); CYP1B1; LTBP2; Consanguinity; Genetic Heterogeneity; trabecular meshwork; anterior chamber angleAbstract
Glaucoma is a leading cause of permanent vision loss in the world, and impacts millions of people. Primary congenital glaucoma (PCG) is a form of congenital glaucoma that is more severe and is a result of defects in the anterior chamber angle and trabecular meshwork. The disease is a common occurrence in groups of people where there is a high incidence of consanguineous marriage, like in Pakistan. The purpose of this study is to investigate the mutational spectrum of the CYP1B1 and LTBP2 genes in patients of primary congenital glaucoma (PCG) from Pakistan. For assessing contribution to PCG, clinical and genetic data were analysed to obtain the disease associated variants. The results showed that mutations in the gene of CYP1B1 were the most frequent genetic defect associated with the disease. These included missense p.Arg390His (p.R390H) which was the most frequent variant. The gene was also shown to have other pathogenic mutations and polymorphisms. Pathogenic variants in the gene for LTBP2 were also detected. While this was not as prevalent as CYP1B1 mutations, these mutations included functionally significant frameshift, missense and nonsense mutations including p.Thr404Serfs*30, p.Asp1010Asn and p.Arg299X. Both these genes have been found to be mutated and this is part of the genetic heterogeneity of primary congenital glaucoma in Pakistan. In conclusion, the importance of CYP1B1 and LTBP2 in the pathogenesis of PCG and the potential for genetic screening for early diagnosis, genetic counselling and better disease management in affected families is highlighted.
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Abu-Amero, K. K., Osman, E. A., Mousa, A., Wheeler, J., Whigham, B., Allingham, R. R., . . . Al-Obeidan, S. A. (2011). Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype-phenotype correlation. Mol Vis, 17, 2911-2919.
Achary, M. S., Reddy, A. B., Chakrabarti, S., Panicker, S. G., Mandal, A. K., Ahmed, N., . . . Nagarajaram, H. A. (2006). Disease-causing mutations in proteins: structural analysis of the CYP1B1 mutations causing primary congenital glaucoma in humans. Biophys J, 91(12), 4329-4339. doi:10.1529/biophysj.106.085498 DOI: https://doi.org/10.1529/biophysj.106.085498
Afzal, R., Firasat, S., Kaul, H., Ahmed, B., Siddiqui, S. N., Zafar, S. N., . . . Afshan, K. (2019). Mutational analysis of the CYP1B1 gene in Pakistani primary congenital glaucoma patients: Identification of four known and a novel causative variant at the 3' splice acceptor site of intron 2. Congenit Anom (Kyoto), 59(5), 152-161. doi:10.1111/cga.12312 DOI: https://doi.org/10.1111/cga.12312
Ali, M., McKibbin, M., Booth, A., Parry, D. A., Jain, P., Riazuddin, S. A., . . . Inglehearn, C. F. (2009). Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet, 84(5), 664-671. doi:10.1016/j.ajhg.2009.03.017 DOI: https://doi.org/10.1016/j.ajhg.2009.03.017
Arshad, A., Alyas, M. A., Arshad, S., & Arshad, U. (2024). Insight into Retinal Dystrophy: Understanding Features and Treatment Strategies. Journal of Health and Rehabilitation Research, 4(2), 175-182. doi:10.61919/jhrr.v4i2.784 DOI: https://doi.org/10.61919/jhrr.v4i2.784
Chouiter, L., & Nadifi, S. (2017). Analysis of CYP1B1 Gene Mutations in Patients with Primary Congenital Glaucoma. J Pediatr Genet, 6(4), 205-214. doi:10.1055/s-0037-1602695 DOI: https://doi.org/10.1055/s-0037-1602695
Faiq, M., Sharma, R., Dada, R., Mohanty, K., Saluja, D., & Dada, T. (2013). Genetic, Biochemical and Clinical Insights into Primary Congenital Glaucoma. J Curr Glaucoma Pract, 7(2), 66-84. doi:10.5005/jp-journals-10008-1140 DOI: https://doi.org/10.5005/jp-journals-10008-1140
Faiq, M. A., Dada, R., Qadri, R., & Dada, T. (2015). CYP1B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract, 9(3), 77-80. doi:10.5005/jp-journals-10008-1189 DOI: https://doi.org/10.5005/jp-journals-10008-1189
Firasat, S., Riazuddin, S. A., Khan, S. N., & Riazuddin, S. (2008). Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma. Mol Vis, 14, 2002-2009.
Gagrani, M., Garg, I., & Ghate, D. (2020). Surgical interventions for primary congenital glaucoma. Cochrane Database Syst Rev, 8(8), Cd008213. doi:10.1002/14651858.CD008213.pub3 DOI: https://doi.org/10.1002/14651858.CD008213.pub3
Guo, L., Moss, S. E., Alexander, R. A., Ali, R. R., Fitzke, F. W., & Cordeiro, M. F. (2005). Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Invest Ophthalmol Vis Sci, 46(1), 175-182. doi:10.1167/iovs.04-0832 DOI: https://doi.org/10.1167/iovs.04-0832
Ho, C. L., & Walton, D. S. (2004). Primary congenital glaucoma: 2004 update. J Pediatr Ophthalmol Strabismus, 41(5), 271-288; quiz 300-271. doi:10.3928/01913913-20040901-11 DOI: https://doi.org/10.3928/01913913-20040901-11
Hussain, R., & Bittles, A. H. (2004). Assessment of association between consanguinity and fertility in Asian populations. J Health Popul Nutr, 22(1), 1-12.
Kabra, M., Zhang, W., Rathi, S., Mandal, A. K., Senthil, S., Pyatla, G., . . . Chakrabarti, S. (2017). Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. Hum Genet, 136(8), 941-949. doi:10.1007/s00439-017-1823-6 DOI: https://doi.org/10.1007/s00439-017-1823-6
Kaur, K., Mandal, A. K., & Chakrabarti, S. (2011). Primary Congenital Glaucoma and the Involvement of CYP1B1. Middle East Afr J Ophthalmol, 18(1), 7-16. doi:10.4103/0974-9233.75878 DOI: https://doi.org/10.4103/0974-9233.75878
Kaushik, S., Luthra-Guptasarma, M., Prasher, D., Dhingra, D., Singh, N., Kumar, A., . . . Pandav, S. S. (2023). CYP1B1 and MYOC variants in neonatal-onset versus infantile-onset primary congenital glaucoma. Br J Ophthalmol, 107(2), 227-233. doi:10.1136/bjophthalmol-2020-318563 DOI: https://doi.org/10.1136/bjophthalmol-2020-318563
Micheal, S., Siddiqui, S. N., Zafar, S. N., Iqbal, A., Khan, M. I., & den Hollander, A. I. (2016). Identification of Novel Variants in LTBP2 and PXDN Using Whole-Exome Sequencing in Developmental and Congenital Glaucoma. PloS one, 11(7), e0159259. doi:10.1371/journal.pone.0159259 DOI: https://doi.org/10.1371/journal.pone.0159259
Ou, Z., Liu, G., Liu, W., Deng, Y., Zheng, L., Zhang, S., & Feng, G. (2018). Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients. Biosci Rep, 38(4). doi:10.1042/bsr20180056 DOI: https://doi.org/10.1042/BSR20180056
Quigley, H. A., & Broman, A. T. (2006). The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol, 90(3), 262-267. doi:10.1136/bjo.2005.081224 DOI: https://doi.org/10.1136/bjo.2005.081224
Reddy, A. B., Kaur, K., Mandal, A. K., Panicker, S. G., Thomas, R., Hasnain, S. E., . . . Chakrabarti, S. (2004). Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients. Mol Vis, 10, 696-702.
Sarfarazi, M., Stoilov, I., & Schenkman, J. B. (2003). Genetics and biochemistry of primary congenital glaucoma. Ophthalmol Clin North Am, 16(4), 543-554, vi. doi:10.1016/s0896-1549(03)00062-2 DOI: https://doi.org/10.1016/S0896-1549(03)00062-2
Shah, M., Bouhenni, R., & Benmerzouga, I. (2022). Geographical Variability in CYP1B1 Mutations in Primary Congenital Glaucoma. J Clin Med, 11(7). doi:10.3390/jcm11072048 DOI: https://doi.org/10.3390/jcm11072048
Song, Y. S., Annalora, A. J., Marcus, C. B., Jefcoate, C. R., Sorenson, C. M., & Sheibani, N. (2022). Cytochrome P450 1B1: A Key Regulator of Ocular Iron Homeostasis and Oxidative Stress. Cells, 11(19). doi:10.3390/cells11192930 DOI: https://doi.org/10.3390/cells11192930
Suri, F., Kalhor, R., Zargar, S. J., Nilforooshan, N., Yazdani, S., Nezari, H., . . . Elahi, E. (2008). Screening of common CYP1B1 mutations in Iranian POAG patients using a microarray-based PrASE protocol. Mol Vis, 14, 2349-2356.
Zenteno, J. C., Hernandez-Merino, E., Mejia-Lopez, H., Matías-Florentino, M., Michel, N., Elizondo-Olascoaga, C., . . . Garcia-Ortiz, J. E. (2008). Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico. J Glaucoma, 17(3), 189-192. doi:10.1097/IJG.0b013e31815678c3 DOI: https://doi.org/10.1097/IJG.0b013e31815678c3
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