Phenotype analysis, molecular genetics and therapeutics of glaucoma: Recent developments and future directions with respect to Pakistan

Paper Details

Research Paper 01/02/2018
Views (169) Download (22)

Phenotype analysis, molecular genetics and therapeutics of glaucoma: Recent developments and future directions with respect to Pakistan

Muhammad Usman, Muhammad Ali, Qaisar Hanif, Muhammad Qasim, Muhammad Ibrahim Rajoka, Muhammad Rashid, Zulqarnain Manzoor, Omer Draz, Tehreem Anwar, Mirza Jawad ul Hasnain
Int. J. Biosci.12( 2), 345-356, February 2018.
Certificate: IJB 2018 [Generate Certificate]


Blindness is a major disability that severely compromises the life quality and makes the individuals unfit for every job. Genetic factors play key role in many types of eye disorders, involving those disorders that are the key reason of blindness amongst infants, children and adults. Glaucoma is a main source of sight loss not only sight and is categorized by enlightened deterioration of the optical nerve and is usually connected with higher intraocular pressure. Without adequate dealing, glaucoma can be developed to optical disability and ultimately sightlessness. Scientists had determined and mapped several genes for glaucoma. Pakistani population is relatively least investigating for genetic diseases as compare to European population. Because of the high degree of consanguinity Pakistani population offers a priceless genetic resource for identifying new genomic regions and to fill gaps in the existing knowledge. In this review, we provide detailed description of genetic and phenotypic heterogeneity of glaucoma disease with respect to Pakistan and also we shed some light on current therapeutic approaches and future directions. Furthermore, we identified 10 consanguineous glaucomatous families of Pakistan with multiple affected individuals and performed their clinical evaluation for better understanding of disease.


Abu-Amero KK, Osman EA, Mousa A, Wheeler J, Whigham B, Allingham RR, Hauser MA, Al-Obeidan SA. 2011. Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype-phenotype correlation. Molecular Vision 17, 2911.

Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, Johnson AT, Khanna CL, Yamamoto T, Mackey DA, Roos BR. 2003. Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. American Journal of Ophthalmology 136, 904-910.

Bakalash S, Shlomo GB, Aloni E, Shaked I, Wheeler L, Ofri R, Schwart M. 2005. T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure. Journal of Molecular Medicine 83, 904-916.

Bashir R, Sanai M, Azeem A, Altaf I, Saleem F, Naz, S. 2014. Contribution of GLC3A locus to Primary Congenital Glaucoma in Pakistani population. Pakistan Journal of Medical Sciences 30, 1341.

Beckerman M. 2002. Modeling and Simulation of Microelectrode-Retina Interactions. Oak Ridge Y-12 Plant, TN (US).

Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, Jabak M, Astle WF, Otterud B, Leppert M, Lupski JR. 1998. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. The American Journal of Human Genetics 62, 325-333.

Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, Astle WF, Lupski JR. 2000. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Human Molecular Genetics 9, 367-374.

Buhrmann RR, Quigley HA, Barron Y, West SK, Oliva MS, Mmbaga BB. 2000. Prevalence of glaucoma in a rural East African population. Investigative Ophthalmology & Visual Science 41, 40-48.

Casson RJ, Chidlow G, Wood JP, Crowston JG, Goldberg I. 2012. Definition of glaucoma: clinical and experimental concepts. Clinical & Experimental Ophthalmology 40, 341-349.

Cheng C-Y, Schache M, Ikram MK, Young TL, Guggenheim JA, Vitart V, MacGregor S, Verhoeven VJ, Barathi VA, Liao J. 2013. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. The American Journal of Human Genetics 93, 264-277.

Christou M, Savas Ü, Spink DC, Gierthy JF, Jefcoate CR. 1994. Co-expression of human CYP1A1 and a human analog of cytochrome P450-EF in response to 2, 3, 7, 8-tetrachloro-dibenzo-pdioxin in the human mammary carcinoma-derived MCF-7 cells. Carcinogenesis 15, 725-732.

Consoli D, McMeekin A, Ramlogan R, Mina A, Tampubolon G, Metcalfe J. 2005. Progress in medicine: The structure and evolution of know-how for the treatment of glaucomea. CRIC Discussion Paper.

Dai X, Nie S, Ke T, Liu J, Wang Q, Liu M. 2008. Two variants in MYOC and CYP1B1 genes in a Chinese family with primary angle-closure glaucoma. Zhonghua yi xue yi chuan xue za zhi= Zhonghua yixue yichuanxue zazhi= Chinese Journal of Medical Genetics 25, 493-496.

Ehrlich JR, Radcliffe NM, Shimmyo M. 2012. Goldmann applanation tonometry compared with corneal-compensated intraocular pressure in the evaluation of primary open-angle Glaucoma. BMC Ophthalmology 12, 52.

Faiq M, Sharma R, Dada R, Mohanty K, Saluja D, Dada T. 2013. Genetic, biochemical and clinical insights into primary congenital glaucoma. Journal of Current Glaucoma Practice 7, 66.

Farkas RH, Grosskreutz CL. 2001. Apoptosis, neuroprotection, and retinal ganglion cell death: an overview. International ophthalmology clinics 41, 111-130.

Fechtner RD, Realini T. 2004. Fixed combinations of topical glaucoma medications. Current Opinion in Ophthalmology 15, 132-135.

Feldman RM. 2004. An evaluation of the fixed-combination of latanoprost and timolol for use in open-angle glaucoma and ocular hypertension. Expert Opinion on Pharmacotherapy 5, 909-921.

Ferris FL, Kassoff A, Bresnick GH, Bailey I. 1982. New visual acuity charts for clinical research. American Journal of Ophthalmology 94, 91-96.

Filla MS, Liu X, Nguyen TD, Polansky JR, Brandt CR, Kaufman PL, Peters DM. 2002. In vitro localization of TIGR/MYOC in trabecular meshwork extracellular matrix and binding to fibronectin. Investigative Ophthalmology & Visual Science 43, 151-161.

Fingert JH, Robin AL, Stone JL, Roos BR, Davis LK, Scheetz TE, Bennett SR, Wassink TH, Kwon YH, Alward WL. 2011. Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Human Molecular Genetics 20, 2482-2494.

Fingert JH, Stone EM, Sheffield VC, Alward WL. 2002. Myocilin glaucoma. Survey of Ophthalmology 47, 547-561.

Fraunfelder F, Keates EU. 2004. Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 111, 109-111.

Frick KD, Foster A. 2003. The magnitude and cost of global blindness: an increasing problem that can be alleviated. American Journal of Ophthalmology 135, 471-476.

Garaci FG, Bolacchi F, Cerulli A, Melis M, Spanò A, Cedrone C, Floris R, Simonetti G, Nucci C. 2009a. Optic nerve and optic radiation neurodegeneration in patients with glaucoma: in vivo analysis with 3-T diffusion-tensor MR imaging. Radiology 252, 496-501.

Garaci FG, Bolacchi F, Cerulli A, Melis M, Spanò A, Cedrone C, Floris R, Simonetti G, Nucci C. 2009b. Optic Nerve and Optic Radiation Neurodegeneration in Patients with Glaucoma: In Vivo Analysis with 3-T Diffusion-Tensor MR Imaging 1. Radiology 252, 496-501.

Gooch N, Molokhia SA, Condie R, Burr RM, Archer B, Ambati BK, Wirostko B. 2012. Ocular drug delivery for glaucoma management. Pharmaceutics 4, 197-211.

Harasymowycz P, Birt C, Gooi P, Heckle L, Hutnik C, Jinapriya D, Shuba L, Yan D, Day R. 2016. Medical management of glaucoma in the 21st Century from a Canadian perspective. Journal of Ophthalmology 2016.

Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutte TR. 1996. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proceedings of the National Academy of Sciences 93, 9776-9781.

Hussain R, Bittles A. 1998. The prevalence and demographic characteristics of consanguineous marriages in Pakistan. Journal of Biosocial Science 30, 261-275.

Inamori Y, Ota M, Inoko H, Okada E, Nishizaki R, Shiota T, Mok J, Oka A, Ohno S, Mizuki N. 2007. The COL1A1 gene and high myopia susceptibility in Japanese. Human Genetics 122, 151-157.

Iqbal S, Khan Z, Shah SA, Khan MY. 2011. Types and presentation of glaucoma. Journal of Postgraduate Medical Institute (Peshawar-Pakistan) 22.

Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, Santner SJ, Tekmal R, Demers L, Pauley R. 2000. Chapter 5: Tissue-specific synthesis and oxidative metabolism of estrogens. JNCI Monographs 2000, 95-112.

Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK, Wilson MR, Gordon MO. 2002. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Archives of Ophthalmology 120, 701-713.

Khan L, Ali M, Qasim M, Jabeen F, Hussain B. 2017. Molecular basis of glaucoma and its therapeutical analysis in Pakistan: an overview. Biomedical Research and Therapy 4, 1210-1227.

Khaw K-T, Wareham N, Bingham S, Luben R, Welch A, Day N. 2004. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Annals of Internal Medicine 141, 413-420.

Kim YY, Jung HR. 1997. Clarifying the nomenclature for primary angle-closure glaucoma. Survey of Ophthalmology 42, 125-136.

Kubota R, Noda S, Wang Y, Minoshima S, Asakawa S, Kudoh J, Mashima Y, Oguchi Y, Shimizu N. 1997. A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: Molecular cloning, tissue expression, and chromosomal mapping. Genomics 41, 360-369.

Kumar A, Basavaraj MG, Gupta SK, Qamar I, Ali AM, Bajaj V, Ramesh T, Prakash DR, Shetty JS, Dorairaj SK. 2007a. Role of CYP1B1, MYOC, OPTN and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian Patients. Molecular Vision 13, 667.

Kumar A, Basavaraj MG, Gupta SK, Qamar I, Ali AM, Bajaj V, Ramesh T, Prakash DR, Shetty JS, Dorairaj SK. 2007b. Role of CYP1B1, MYOC, OPTN, and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian Patients. Mol Vis 13, 667-676.

Lau J, Lee V, Fan D, Lau M, Michon J. 2002. Knowledge about cataract, glaucoma, and age related macular degeneration in the Hong Kong Chinese population. British Journal of Ophthalmology 86, 1080-1084.

Mc Brien NA, Cornell LM, Gentle A. 2001. Structural and ultrastructural changes to the sclera in a mammalian model of high myopia. Investigative Ophthalmology & Visual Science 42, 2179-2187.

Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, Liebmann J, Ritch R, Héon E, Crick RP, Child A. 2005. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22. 1. Human Molecular Genetics 14, 725-733.

Mookherjee S, Chakraborty S, Vishal M, Banerjee D, Sen A, Ray K. 2011. WDR36 variants in East Indian primary open-angle glaucoma patients.

Noda S, Mashima Y, Obazawa M, Kubota R, Oguchi Y, Kudoh J, Minoshima S, Shimizu N. 2000. Myocilin expression in the astrocytes of the optic nerve head. Biochemical and Biophysical Research Communications 276, 1129-1135.

Norman RE, Flanagan JG, Sigal IA, Rausch SM, Tertinegg I, Ethier CR. 2011. Finite element modeling of the human sclera: influence on optic nerve head biomechanics and connections with glaucoma. Experimental Eye Research 93, 4-12.

Ohlmann A, Tamm E. 2002. Die Rolle von Myocilin bei der Pathogenese des primären Offenwinkelglaukoms. Der Ophthalmologe 99, 672-677.

Quigley HA, Broman AT. 2006. The number of people with glaucoma worldwide in 2010 and 2020. British Journal of Ophthalmology 90, 262-267.

Rein DB, Zhang P, Wirth KE, Lee PP, Hoerger TJ, McCall N, Klein R, Tielsch JM, Vijan S, Saaddine J. 2006. The economic burden of major adult visual disorders in the United States. Archives of Ophthalmology 124, 1754-1760.

Rezaie T, Stoilov I, Sarfarazi M. 2007. Embryonic expression of the optineurin (glaucoma) gene in different stages of mouse development. Mol. Vis 13, 1446-1450.

Rizzo MI, Greco A, De Virgilio A, Gallo A, Taverniti L, Fusconi M, Conte M, Pagliuca G, Turchetta R, de Vincentiis M. 2017. Glaucoma: recent advances in the involvement of autoimmunity. Immunologic Research 65, 207-217.

Sarfarazi M. 1997. Recent advances in molecular genetics of glaucomas. Human Molecular Genetics 6, 1667-1677.

Sarfarazi M, Stoilov I. 2000. Molecular genetics of primary congenital glaucoma. Eye 14, 422-428.

Shastry BS. 2013. Genetic susceptibility to primary angle closure glaucoma (PACG). Discovery Medicine 15, 17-22. 

Sheikh SA, Waryah AM, Narsani AK, Shaikh H, Gilal IA, Shah K, Qasim M, Memon AI, Kewalramani P, Shaikh N. 2014. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: novel variants and genotype-phenotype correlations. Molecular Vision 20, 991.

Sutter TR, Tang YM, Hayes CL, Wo Y-Y, Jabs EW, Li X, Yin H, Cody CW, Greenlee WF. 1994. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. Journal of Biological Chemistry 269, 13092-13099.

Tello C, Rothman R, Ishikawa H, Ritch R. 2000. Differential diagnosis of the angle-closure glaucomas. Ophthalmology Clinics 13, 443-453.

Weinreb RN, Aung T, Medeiros FA. 2014. The pathophysiology and treatment of glaucoma: a review. Jama 311, 1901-1911.

Weisschuh N, Schiefer U. 2003. Progress in the genetics of glaucoma, Genetics in Ophthalmology. Karger Publishers pp. 83-93.

Wiggs JL, Allingham RR, Vollrath D, Jones KH, De La Paz M, Kern J, Patterson K, Babb VL, Del Bono EA, Broomer BW. 1998. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. American Journal of Human Genetics 63, 1549.

Wiggs JL, Lynch S, Ynagi G, Maselli M, Auguste J, Del Bono E, Olson L, Haines J. 2004. A genomewide scan identifies novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12. The American Journal of Human Genetics 74, 1314-1320.

Zhou X-M, Yin Y, Fan N, Cheng H-B, Li X-H, Wang Y, Yu W-H, Cai S-P, Liu X-Y. 2013. Single nucleotide polymorphism of MYOC affected the severity of primary open angle glaucoma. International Journal of Ophthalmology 6, 264.