The genetics associated with Primary Congenital Glaucoma

Ali Imran, Muhammad Umer Khan, Umer Nasir, Qasim Qayyum, Rubab Hector, Raima Rehman, Atif Amin Baig


Glaucoma is a progressive optic neuropathy; increased intraocular pressure (IOP) is a modifiable risk factor for primary congenital glaucoma (PCG). Increase IOP causes retinal and optic nerve compression and leads to gradual and irreversible loss of eyesight if left untreated. It is the second most leading cause of blindness. PCG mainly affects children up to the age of three years, and symptoms include epiphora, photalgia, swollen eyes, opaque corneas, blepharospasm, rupture in the retina and ocular nerve damage due to IOP. Early detection, management, and treatment are the keys to preventing vision loss from glaucoma. Many mutations have been discovered in Cytochrome P450 1B1 (CYP1B1) gene to be responsible for causing PCG, and there are still a lot of mutations to be discovered. In this review, we will discuss the genetic aspects of PCG and the most frequent mutations responsible for PCG in Pakistani children. PCG can be handled by decreasing IOP either by medication or by surgery. Genetic counselling plays a significant role in the establishment of proper management of PCG.

Keywords: Primary Congenital Glaucoma; IOP; Cyp1b1; Mutations

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Pemberton SG, Frey RW. Trace fossil nomenclature and the Planolites-Palaeophycus dilemma. Journal of Paleontology, (1982); 843-881.

Dictionary OE. Oxford english dictionary. Simpson, JA & Weiner, ESC, (1989).

Sarfarazi M, Stoilov I, Schenkman J. Genetics and biochemistry of primary congenital glaucoma. Ophthalmology clinics of North America, (2003); 16(4): 543-554.

deLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Survey of Ophthalmology, (1983); 28(1): 1-19.

Quigley HA. Open-angle glaucoma. New England Journal of Medicine, (1993); 328(15): 1097-1106.

Weinreb RN, Khaw PT. Primary open-angle glaucoma. The Lancet, (2004); 363(9422): 1711-1720.

Anderson J (1939) Aetiology: Hydrophthalmia or Congenital Glaucoma. London, England: Cambridge University Press.

Hewitt A, Mackinnon J, Elder J, Giubilato A, Craig J, et al. Familial transmission patterns of infantile glaucoma in Australia. Investigative Ophthalmology & Visual Science, (2005); 46(13): 3207-3207.

Ko F, Papadopoulos M, Khaw PT (2015) Primary congenital glaucoma. Progress in brain research: Elsevier. pp. 177-189.

Rulli E, Quaranta L, Riva I, Poli D, Hollander L, et al. Visual field loss and vision-related quality of life in the Italian Primary Open Angle Glaucoma Study. Scientific reports, (2018); 8(1): 619.

Rashid M, Yousaf S, Sheikh SA, Sajid Z, Shabbir AS, et al. Identities and frequencies of variants in CYP1B1 causing primary congenital glaucoma in Pakistan. Molecular vision, (2019); 25: 144-154.

Badawi AH, Al-Muhaylib AA, Al Owaifeer AM, Al-Essa RS, Al-Shahwan SA. Primary congenital glaucoma: An updated review. Saudi Journal of Ophthalmology, (2019); 33(4): 382-388.

Fan BJ, Wiggs JL. Glaucoma: genes, phenotypes, and new directions for therapy. The Journal of clinical investigation, (2010);120(9):3064-72.

de Alencar Gomes H, de Souza Moreira B, Sampaio RF, Furtado SRC, Cronemberger S, et al. Gait parameters, functional mobility and fall risk in individuals with early to moderate primary open angle glaucoma: a cross-sectional study. Brazilian Journal of Physical Therapy, (2018); 22(5): 376-382.

Yang Y, Zhang L, Li S, Zhu X, Sundaresan P. Candidate gene analysis identifies mutations in CYP1B1 and LTBP2 in Indian families with primary congenital glaucoma. Genetic Testing and Molecular Biomarkers, (2017); 21(4): 252-258.

Lewis CJ, Hedberg-Buenz A, DeLuca AP, Stone EM, Alward WL, et al. Primary congenital and developmental glaucomas. Human Molecular Genetics, (2017); 26(R1): R28-R36.

Abu-Amero KK, Edward DP (2017) Primary congenital glaucoma. GeneReviews®[Internet]: University of Washington, Seattle.

Jünemann A, Hohberger B, Rech J, Sheriff A, Fu Q, et al. Agonistic autoantibodies to the β2-adrenergic receptor involved in the pathogenesis of open-angle glaucoma. Frontiers in Immunology, (2018); 9: 145.

Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. New England Journal of Medicine, (2009); 360(11): 1113-1124.

Gilbert CE, Canovas R, de Canovas RK, Foster A. Causes of blindness and severe visual impairment in children in Chile. Developmental Medicine & Child Neurology, (1994); 36(4): 326-333.

Zhao J. Prevention of blindness is still the great challenge faced by Chinese ophthalmology. Chinese Journal of Ophthalmology, (2009); 45(9): 769-771.

Sarfarazi M, Akarsu NA, Hossain A, Turacli EM, Aktan GS, et al. Assignment of a locus (GLC3A) for primary congenital glaucoma (Buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics, (1995); 30(2): 171-177.

Chen Y, Jiang D, Yu L, Katz B, Zhang K, et al. CYP1B1 and MYOC mutations in 116 Chinese patients with primary congenital glaucoma. Archives of Ophthalmology, (2008); 126(10): 1443-1447.

Stoilov I, Akarsu AN, Alozie I, Child A, Barsoum-Homsy M, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. The American Journal of human genetics, (1998); 62(3): 573-584.

López-Garrido M-P, Medina-Trillo C, Morales-Fernandez L, Garcia-Feijoo J, Martínez-de-la-Casa JM, et al. Null CYP1B1 genotypes in primary congenital and nondominant juvenile glaucoma. Ophthalmology, (2013); 120(4): 716-723.

Benedict TWG Abhandlungen aus dem Gebiete der Augenheilkunde. 1842; 1; Freund.

Jaafar MS. Care of the infantile glaucoma patient. Ophthalmology annual, (1988); 715-37.

Papadopoulos M, Cable N, Rahi J, Khaw PT. The British infantile and childhood glaucoma (BIG) eye study. Investigative Ophthalmology & Visual Science, (2007); 48(9): 4100-4106.

Qayyum M, Zia WT, Khan MU. An Insight to Primary Congenital Glaucoma. Critical Review in Eukaryotic Gene Expression, (2020); 30(1); 39-43.

Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, et al. 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, (1998); 62(2): 325-333.

Genĉík A. Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Developments in Ophthalmology, (1989); 1676-115.

Genčík A, Genčíkova A, Ferak V. Population genetical aspects of primary congenital glaucoma. I. Incidence, prevalence, gene frequency, and age of onset. Human Genetics, (1982); 61(3): 193-197.

MacKinnon JR, Giubilato A, Elder JE, Craig JE, Mackey DA. Primary infantile glaucoma in an Australian population. Clinical & Experimental Ophthalmology, (2004); 32(1): 14-18.

Tamçelik N, Atalay E, Bolukbasi S, Çapar O, Ozkok A. Demographic features of subjects with congenital glaucoma. Indian Journal of Ophthalmology, (2014); 62(5): 565.

Alanazi FF, Song JC, Mousa A, Morales J, Al Shahwan S, et al. Primary and secondary congenital glaucoma: baseline features from a registry at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. American Journal of Ophthalmology, (2013); 155(5): 882-889. e881.

Chouiter L, Nadifi S. Analysis of CYP1B1 gene mutations in patients with primary congenital glaucoma. Journal of Pediatric Genetics, (2017); 6(04): 205-214.

Fung DS, Roensch MA, Kooner KS, Cavanagh HD, Whitson JT. Epidemiology and characteristics of childhood glaucoma: results from the Dallas Glaucoma Registry. Clinical Ophthalmology (Auckland, NZ), (2013);7: 1739-46.

Stoilov I, Jansson I, Sarfarazi M, Schenkman JB. Roles of cytochrome p450 in development. Drug Metabolism and Drug Interactions, (2001); 18(1): 33-56.

Li F, Zhu W, Gonzalez FJ. Potential role of CYP1B1 in the development and treatment of metabolic diseases. Pharmacology & Therapeutics, (2017); 178: 18-30.

Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Human Molecular Genetics, (1997); 6(4): 641-647.

Zhao Y, Wang S, Sorenson CM, Teixeira L, Dubielzig RR, et al. Cyp1b1 mediates periostin regulation of trabecular meshwork development by suppression of oxidative stress. Molecular and Cellular Biology, (2013); 33(21): 4225-4240.

Mookherjee S, Acharya M, Banerjee D, Bhattacharjee A, Ray K. Molecular basis for involvement of CYP1B1 in MYOC upregulation and its potential implication in glaucoma pathogenesis. PloS one, (2012); 7(9): e45077.

Tang YM, Wo Y-YP, Stewart J, Hawkins AL, Griffin CA, et al. Isolation and characterization of the human cytochrome P450 CYP1B1 gene. Journal of Biological Chemistry, (1996); 271(45): 28324-28330.

Faiq M, Sharma R, Dada R, Mohanty K, Saluja D, et al. Genetic, biochemical and clinical insights into primary congenital glaucoma. Journal of Current Glaucoma Practice, (2013); 7(2): 66-84.

Li N, Zhou Y, Du L, Wei M, Chen X. Overview of Cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. Experimental Eye Research, (2011); 93(5): 572-579.

Panicker SG, Mandal AK, Reddy AB, Gothwal VK, Hasnain SE. Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Investigative Ophthalmology & Visual Science, (2004); 45(4): 1149-1156.

Prokudin I, Simons C, Grigg JR, Storen R, Kumar V, et al. Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. European Journal of Human Genetics, (2014); 22(7): 907-15.

Kelberman D, Islam L, Jacques TS, Russell-Eggitt I, Bitner-Glindzicz M, et al. CYP1B1-Related Anterior Segment Developmental Anomalies: Novel Mutations for Infantile Glaucoma and Von Hippel's Ulcer Revisited. Ophthalmology, (2011); 118(9): 1865-1873.

Curry SM, Daou AG, Hermanns P, Molinari A, Lewis RA, et al. Cytochrome P4501B1 mutations cause only part of primary congenital glaucoma in Ecuador. Ophthalmic Genetics, (2004); 25(1): 3-9.

Reis LM, Tyler RC, Weh E, Hendee KE, Kariminejad A, et al. Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. Molecular vision, (2016); 22: 1229-1238.

Khan MU, Rehman R, Kaul H, Mahmood S, Ammar A. Mutational analysis of CYP1B1 gene in Pakistani pediatric patients affected with Primary Congenital Glaucoma. Advancements in Life Sciences, (2019); 7(1): 32-37.

Rauf B, Irum B, Kabir F, Firasat S, Naeem MA, et al. A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent. Human Genome Variation, (2016); 3:16021.

Firasat S, Kaul H, Ashfaq UA, Idrees S. In silico analysis of five missense mutations in CYP1B1 gene in Pakistani families affected with primary congenital glaucoma. International Ophthalmology, (2018); 38(2): 807-814.

Sheikh SA, Waryah AM, Narsani AK, Shaikh H, Gilal IA, et al. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: novel variants and genotype-phenotype correlations. Molecular vision, (2014); 20991.

Ali M, McKibbin M, Booth A, Parry DA, Jain P, et al. Null mutations in LTBP2 cause primary congenital glaucoma. The American Journal of Human Genetics, (2009); 84(5): 664-671.

Narooie-Nejad M, Paylakhi SH, Shojaee S, Fazlali Z, Rezaei Kanavi M, et al. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Human Molecular Genetics, (2009); 18(20): 3969-3977.

Vehviläinen P, Hyytiäinen M, Keski-Oja J. Latent transforming growth factor-β-binding protein 2 is an adhesion protein for melanoma cells. Journal of Biological Chemistry, (2003); 278(27): 24705-24713.

Hyytiäinen M, Keski-Oja J. Latent TGF-β binding protein LTBP-2 decreases fibroblast adhesion to fibronectin. The Journal of Cell Biology, (2003); 163(6): 1363-1374.

Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A, et al. Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J Cell Biol, (2007); 176(7): 1061-1071.

Fujikawa Y, Yoshida H, Inoue T, Ohbayashi T, Noda K, et al. Latent TGF-β binding protein 2 and 4 have essential overlapping functions in microfibril development. Scientific reports, (2017); 7: 43714.

Hirani R, Hanssen E, Gibson MA. LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein. Matrix Biology, (2007); 26(4): 213-

Inoue T, Ohbayashi T, Fujikawa Y, Yoshida H, Akama TO, et al. Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils. Human Molecular Genetics, (2014); 23(21): 5672-5682.

Kizhatil K, Ryan M, Marchant JK, Henrich S, John SW. Schlemm's canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PLoS Biology, (2014); 12(7): e1001912.

Park D-Y, Lee J, Park I, Choi D, Lee S, et al. Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity. The Journal of Clinical Investigation, (2014); 124(9): 3960-3974.

Sung KR, Kim JS, Wollstein G, Folio L, Kook MS, et al. Imaging of the retinal nerve fibre layer with spectral domain optical coherence tomography for glaucoma diagnosis. British Journal of Ophthalmology, (2011); 95(7): 909-914.

Dietlein TS, Jacobi PC, Krieglstein GK. Assessment of diagnostic criteria in management of infantile glaucoma. International ophthalmology, (1996); 20(1-3): 21-27.

Beck AD. Diagnosis and management of pediatric glaucoma. Ophthalmology Clinics of North America, (2001); 14(3): 501-512.

Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. American Journal of Health-System Pharmacy, (2005); 62(7): 691-699.

Chan JYY, Choy BN, Ng AL, Shum JW. Review on the management of primary congenital glaucoma. Journal of Current Glaucoma Practice, (2015); 9(3): 92-99.

Turaçh ME, Aktan G, Idil A. Medical and surgical aspects of congenital glaucoma. Acta Ophthalmologica Scandinavica, (1995); 73(3): 261-263.

Al Faran MF, Tomey KF, Al Mutlaq FA. Cyclocryotherapy in selected cases of congenital glaucoma. Ophthalmic Surgery, Lasers and Imaging Retina, (1990); 21(11): 794-798.

Wagle NS, Freedman SF, Buckley EG, Davis JS, Biglan AW. Long-term outcome of cyclocryotherapy for refractory pediatric glaucoma. Ophthalmology, (1998); 105(10): 1921-1927.

Al-Haddad CE, Freedman SF. Endoscopic laser cyclophotocoagulation in pediatric glaucoma with corneal opacities. Journal of American Association for Pediatric Ophthalmology and Strabismus, (2007); 11(1): 23-28.


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