About MEAJO | Editorial board | Search | Ahead of print | Current Issue | Archives | Instructions to authors | Online submission | Subscribe | Advertise | Contact | Login 
Middle East African Journal of Ophthalmology Middle East African Journal of Ophthalmology
Users Online: 621   Home Print this page Email this page Small font sizeDefault font sizeIncrease font size


 
  Table of Contents 
ORIGINAL ARTICLE
Year : 2019  |  Volume : 26  |  Issue : 4  |  Page : 203-209  

Investigation of CYP1B1 gene involvement in primary congenital glaucoma in Iraqi children


1 Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kerbala, Kerbala, Iraq
2 Department of Chemistry, College of Science, Mustansiriyah University, Baghdad, Iraq
3 Department of Glaucoma, Ibn Al-Haitham Teaching Eye Hospital, Baghdad, Iraq
4 Department of Biology, College of Science, University of Anbar, Anbar, Iraq

Date of Submission30-Apr-2019
Date of Acceptance24-Dec-2019
Date of Web Publication29-Jan-2020

Correspondence Address:
Dr. Suzanne Jubair
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kerbala, Kerbala
Iraq
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/meajo.MEAJO_116_19

Rights and Permissions
   Abstract 


PURPOSE: Primary congenital glaucoma (PCG) is a severe type of glaucoma that occurs early in life. PCG is usually inherited in an autosomal recessive pattern. Cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) gene is reported to be PCG-related gene. It codes for the CYP1B1 enzyme which is considered as phase I xenobiotic-metabolizing enzyme and its function is related to the eye oxidative homeostasis and correspondingly to the normal development of the eye. This is the first genetic study in Iraq that investigates the CYP1B1 polymorphisms behind the PCG disease.
METHODS: Genomic DNA was extracted from the whole blood of 100 unrelated Iraqi PCG patients and 100 healthy children, all of them were aged between 1 month and 3 years. All the coding sequence of CYP1B1 gene was amplified using polymerase chain reaction; restriction fragment length polymorphism was used to follow G61E and E229K mutations. Direct sequencing was performed to screen for other mutations.
RESULTS: CYP1B1 mutations were identified in 78 (78%) of the patients. We detected a total of eight mutations: Four missense mutations (c.182G>A, c.685G>A, g.6813G>A, and g.6705G>A), one silence mutation (D449D) and three insertions (g.10068ins10069, g.10138ins10139, and g.10191ins10192). Five mutations (g.6813G>A, g.6705G>A, g.10068ins10069, g.10138ins10139, and g.10191ins10192) are novel. G61E is the only mutation that was detected in patients merely.
CONCLUSIONS: CYP1B1 mutation (G61E) is considered as PCG-related allele in the Iraqi population.

Keywords: Cytochrome P450, family 1, Iraqi population, polymorphism, polypeptide 1 gene, primary congenital glaucoma, subfamily B


How to cite this article:
Jubair S, N. Al-Rubae'i SH, M. Al-Sharifi AN, Jabbar Suleiman AA. Investigation of CYP1B1 gene involvement in primary congenital glaucoma in Iraqi children. Middle East Afr J Ophthalmol 2019;26:203-9

How to cite this URL:
Jubair S, N. Al-Rubae'i SH, M. Al-Sharifi AN, Jabbar Suleiman AA. Investigation of CYP1B1 gene involvement in primary congenital glaucoma in Iraqi children. Middle East Afr J Ophthalmol [serial online] 2019 [cited 2020 Jul 3];26:203-9. Available from: http://www.meajo.org/text.asp?2019/26/4/203/277258




   Introduction Top


Glaucoma is a heterogeneous group of ocular disorder that includes optic nerve degeneration, when left untreated, lead to irreversible loss of vision.[1] Almost 15% of blindness worldwide is due to glaucoma. It is categorized under three broad types; primary congenital glaucoma (PCG), closed-angle glaucoma, and primary open-angle glaucoma.[2],[3] PCG is an aggressive type of glaucoma occurs early in life (from birth up to 3 years in age).[4] It is considered as an autosomal recessive disorder. PCG dominance differs from 1:10,000 for the Western communities, 1:3300 for Southern India, and 1:2500 for Saudi Arabia to 1:1250 for the Slovakia Gypsy population,[5],[6] suggesting a strong genetic role in etiology. PCG is caused by developing anomalies in the trabecular meshwork (TM) and the anterior chamber angle of the eye.[1],[7] These anomalies cause impairment in the aqueous humor (AH) outflow leading to elevated intraocular pressure (IOP), which causes optic nerve damage and when left without treatment, permanent blindness.[4]

PCG is considered as a genetically heterogeneous disorder occurring in families and sporadically. Four loci were identified to be related to the disease by linkage analysis; GLC3A which belongs to 2p22-p21, GLC3B belongs to 1p36.2-36.1, GLC3C belongs to14q24.3, and GLC3D belongs to 14q24.2-24.3.[8],[9],[10] The GLC3A was characterized to harbor mutations in Cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) gene.[11]

Mutations in CYP1B1 were detected in over 85% of families affected with PCG in Slovakia, Turkey, and Saudi Arabia;[12],[13] they were reported to be disease-related in the Japanese, Indian, Pakistani, Omani, and Moroccan populations.[14],[15],[16] CYP1B1 gene comprises three exons (371, 1044, and 3707 bp) and two introns (390 and 3032 bp).[17]

This study was designed to examine the role of CYP1B1 mutations in the pathogenesis of PCG in Iraqi children. This is the first genetic study in Iraq that investigates the CYP1B1 polymorphisms behind the PCG disease.


   Methods Top


Study subjects

This study follows the principles of the Helsinki Declaration, and it was approved by the Ethics Committee, Department of Chemistry, College of Science, Mustansiriyah University, Baghdad, Iraq. The blood samples were taken after informed consent of the participants before their inclusion in the study. The affected pediatric were recruited from Ibn Al-Haitham Teaching Eye Hospital, Baghdad, Iraq, while the healthy children were volunteers. All the patients were diagnosed by glaucoma specialist, the standers that were adopted to diagnose PCG are as follows: age of onset runs between 1st day and 3 years, enlarged cornea so the parameter was bigger than 11 mm, elevated IOP (over 21 mmHg) and increased cup-to-disc ratio. Patients have other ocular anomalies, such as anterior segment dysgenesis, aniridia, neurofibromatosis, Sturge– Weber syndrome More Details, and congenital hereditary endothelial dystrophy were excluded from the study.

One hundred unrelated Iraqi PCG affected pediatric (58 males and 42 females) were included in this study and 100 unrelated healthy children (60 males and 40 females) from the same ethnicity without any systemic or ocular disease were served as controls. All the patients and controls aged between 1 month and 3 years. Five milliliter of venous blood was taken from the enrolled children by using plastic disposable syringes and were kept in Ethylenediaminetetraacetic acid (EDTA) tubes and stored at −20°C until used in genetic analysis.

Mutation analysis

Genomic DNA was extracted from whole blood using the genomic DNA extraction kit according to the instructions of the manufacturer (Geneaid, Biotech, Taiwan). The DNA purity and concentration were measured by a nanodrop (BioDrop μLITE, BioDrop co., UK), while the DNA integrity was checked using 0.8% agarose gel electrophoresis, which is prestained with ethidium bromide (0.7 μg/ml) in Tris-Borate-Ethylenediaminetetraacetic acid (TBE) buffer.

The coding region of CYP1B1 gene was amplified using three overlapping primers scheduled in [Table 1]. The lyophilized primers were purchased from Bioneer, South Korea. The polymerase chain reaction (PCR) reaction was performed using a total of 25 μl PCR reaction mixture that contains 3 μl (100 ng of genomic DNA), 2 μl (20 pmol/l) for both forward and reverse primers, 13 μl of free DNAase distilled water, and 5 μl PCR premix from Bioneer, South Korea. Each 5 μl of PCR premix contains 250 μM of dNTPs, 1 U of Top DNA polymerase, 30 mM of KCl, 10 mM of Tris-HCl (pH 9.0), and 1.5 mM of MgCl2. The following program was applied in PCR thermocycler (MyGenieTM 96/384 Thermal Block, Bioneer, South Korea): initial denaturation at 95°C for 5 min, thirty cycles of amplification (denaturation at 94°C for 45 s, annealing at primer-specific annealing temperature [Table 1] for 45 s, extension at 72°C for 1 min, and final extension at 72°C for 10 min). Amplification was verified by electrophoresis on 1.5% agarose gel prestained with ethidium bromide (0.5 mg/ml). Three DNA fragments (776 bp, 757 bp and 872 bp) was selected for amplification, and they supposed to cover all the coding region on exon two and exon three of CYP1B1 gene. Restriction fragment length polymorphism (RFLP)-PCR technique was used to identify the mutations on exon two (G61E and E229K). RFLP-PCR detection for G61E and E229K was done using the restriction endonucleases; TaqI and EarI respectively according to the manufacturer's instruction, New England Biolabs, UK. The three PCR fragments were commercially sequenced according to instruction manuals of the sequencing company, Macrogen Inc. Geumchen, Seoul, South Korea.
Table 1: Polymerase chain reaction primers used to amplify CYP1B1 gene

Click here to view


Statistical analysis

Statistical analysis system-2012 program (SAS-2012, Statistical Analysis System, Version 9.1th ed. SAS. Inst. Inc. Cary. North Carolina, USA) was used for the statistical analysis of the study parameters. T-test used to obtain the mean and standard deviation for the measured parameters.


   Results Top


The results [Table 2] showed the detection of a total of eight mutations: Three missense mutations (G61E, E2229K and g.6705G>A), one silent mutation (D449D), three insertion mutations (g.10068ins10069, g.10138ins10139, and g.10191ins10192), and one intronic missense mutation (g.6813G>A). Five mutations (g.6705G>A, g.6813G>A, g.10068ins10069, g.10138ins10139, and g. 10191ins10192) were novel. E229K was detected only in a heterozygous state in 9 (9%) of the patients and in 7 (7%) of the controls. G61E was detected in 78 (78%) of the patients (homozygous 65 [65%] and heterozygous 13 [13%]), while its distribution in the controls was 0%. The detection of G61E and E229K mutations was done by using the RFLP-PCR technique and direct sequencing, while the other mutations was detected only by the direct sequencing. In case of G61E, a 776 bp PCR fragment was digested with TaqI endonuclease, three pieces (630, 75, and 71 bp) were obtained in the case of the wild type, four pieces (322, 308, 75, and 71 bp) were obtained in case of homozygous mutant type and seven pieces (appeared as five bands); 630, 322, 308, two bands of 75 and two bands of 71 bp were obtained in case of heterozygous mutant type as shown in [Figure 1]a. For the detection of E229K, EarI endonuclease was used. In case of the wild type, three pieces (359, 232, and 166 bp) were obtained, while in the heterozygous mutant type, five pieces (591, 359, 232, and 2 pieces of 166 bp) were obtained [Figure 1]b, whereas homozygous mutant type was not detected in the study groups. G61E and E229K were confirmed by performing sequencing using Sanger protocol, all the other single-nucleotide polymorphisms (SNPs) were detected by Sanger sequencing as well as shown in [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g, [Figure 2]h.
Table 2: Analysis of the single-nucleotide polymorphisms detected in primary congenital glaucoma patients and controls

Click here to view
Figure 1: (a) Restriction fragment length polymorphism polymerase chain reaction genotyping of G61E mutation using TaqI endonuclease on 3% agarose gel. M: 50 bp DNA marker. Lane 1 shows negative control. Lanes 2–6, 8–10, and 12 show the wild type. Lanes 7 and 13 show the homozygous mutant type. Lane 11 shows the heterozygous mutant type. (b) Restriction fragment length polymorphism polymerase chain reaction genotyping of E229K mutation using EarI endonuclease on 3% agarose gel. M: 25 bp DNA marker. Lane 1 shows negative control. Lanes 3, 4, 6, 7, 9, and 11 show the wild type. Lanes 2, 5, 8, 10, and 12 show heterozygous mutant type

Click here to view
Figure 2: Direct sequencing of the CYP1B1 gene coding sequence using Sanger protocol. (a) wild type pattern (G/G) regarding G61E single-nucleotide polymorphism. (b) Heterozygous mutant type (G/A) of G61E. (c) Homozygous mutant type (A/A) of G61E. (d) wild type pattern (G/G) regarding E229K single-nucleotide polymorphism. (e) Heterozygous mutant type (G/A) of E229K. (f) wild type pattern regarding D449D single-nucleotide polymorphism (T/T). (g) Heterozygous mutant type (T/C) of D449D. (h) Homozygous mutant type (C/C) of D449D

Click here to view



   Discussion Top


This is the first genetic study in Iraq that investigates the CYP1B1 polymorphisms behind the PCG. We selected CYP1B1 gene to be screened for mutations in our PCG patients because it is considered as the most PCG-related gene in Middle East countries.[19],[20],[21] The entire coding region (1626 bp located in exons two and exon three)[22] was screened for mutations because all the reported pathogenic mutations are located in these two exons.[16]

CYP1B1 gene encodes a monooxygenase CYP1B1 enzyme that considered as phase I metabolizing enzyme, able to metabolize xenobiotics[23] and also endogenous compounds such as retinoids, estrogen, and testosterone.[23],[24] CYP1B1 enzyme catalyzes several reactions involved in the endogenous compounds metabolism that include retinals, 17 β-estradiol, melatonin, and arachidonic acid.[25] CYP1B1 was reported to be included in the synthesis pathway of retinoic acid.[26],[27] Functional analysis of CYP1B1 mutations associated with PCG showed irregular metabolism of retinol by distorted proteins.[28] CYP family of enzymes includes 70%–80% of the total phase I xenobiotic metabolizing enzymes (XMEs).[29] Phase I XMEs are known for their ability of both metabolic activation and detoxication. The metabolic activation of xenobiotics regularly leads to create electrophilic intermediates. Phase II XMEs help the electrophilic intermediates to conjugate with moieties such as acetate, sulfate, mercapturic acid, glutamine, glycine, and glucoside, yielding very hydrophilic compounds that can be easily expelled to complete the cycle of detoxication.[30] Even though the united effects of phase I and phase II XMEs mostly result in the detoxication of destructive chemical compounds, on the way from the parent compound to the expelled product, there is a chance for reactive oxygenated intermediates to be formed through the CYP-mediated reactions, therefore affecting the oxidative stress state of the cells.[30]

CYP1B1 is widely expressed in TM and the ciliary body in the eye. The development of the TM, which is the most important tissue in the case of PCG, depends critically on the CYP1B1 enzyme; therefore, mutations that are detrimental to the function of CYP1B1 can be disrupting to the proper development of the TM, which in turn would obstruct AH outflow, resulting in the elevation of IOP.[31],[32]

The AH in human glaucoma patients has a significant reduction in total anti-oxidant capacity (TAC) because of the increased oxidative stress in the glaucomatous eye, elevated oxidative stress can cause trabecular dysgenesis that leads to PCG.[33] Under H2O2 treatment (high oxidative stress), the TM cells are less viable indicating deficiency in antioxidant capacity to reduce reactive oxygen species (ROS) in the cell. CYP1B1 enzyme activity straightly determines the oxidative status of the TM cells; in other words, CYP1B1 deficiency directly leads to increased oxidative stress in the glaucomatous eye.[34],[35],[36] On the other hand, it was reported that higher CYP1B1 enzymatic activity causes 4-OH-estradiol accumulation leading to the generation of quinones, which encourage the formation of ROS, increased oxidative stress may cause cell death in TM and retinal ganglion cells.[25]

CYP1B1 Mutations were found in 78% of our patients' group, this ratio is considered comparable to the Omani (78%), Iranian (78%), and Saudi (76%) populations[19],[20],[21],[37] and more than the ratio (47%) reported for the Moroccan population.[31]

We found that E229K SNP, which is existed in a heterozygous model only, is detected both in patients and controls with close ratios (9% for the patients and 7% for the controls) [Table 2].

By combining the results obtained from our previous report, in which we investigated the impact of oxidative stress in PCG,[38] with the results obtained from the current study it can be concluded that there is no influence for the presence of E229K SNP on the CYP1B1 enzyme, which ranged between 0.822 ± 0.20 ng/ml in the absence of the SNP and 0.871 ± 0.12 ng/ml for the heterozygous mutant type of E229K mentioning that homozygous mutant type was not detected in our study participants. In the same manner and as a result for the CYP1B1 enzyme function TAC and malondialdehyde (MDA) which considered as biochemical parameters reflecting the oxidative state, were measured and there were no significant differences in TAC and MDA in case of the presence or absence of E229K SNP [Table 3]. These facts may exclude E229K from being a disease-related allele. The obtained result is consent with the findings of El-Gayar et al. who ruled out heterozygous E229K from being a cause for PCG in one of their study families,[21] many other studies also reported that heterozygous E229K is found in the patients and healthy carriers.[39],[40] On the other hand, other studies reported that homozygous and compound heterozygous E229K alleles are associated with severe phenotype.[9],[16],[18],[41] Furthermore, López-Garrido et al. stated that heterozygous E229K could increase the susceptibility for the development of primary open-angle glaucoma in the Spanish population.[42]
Table 3: The correlation between CYP1B1 single-nucleotide polymorphisms with CYP1B1 enzyme, total anti-oxidant capacity, and malondialdehyde concentrations

Click here to view


A silent mutation D449D is another SNP that was detected in our study groups, it was detected in both patients and controls and this agrees with an earlier report by Stoilov et al. who also detected D449D in both PCG patients and healthy individuals in the Brazil population.[43] We found that D449D is similar to E229K SNP, has no influence on the CYP1B1 enzyme, TAC and MDA levels and it may do not considered as pathogenic SNP. Unlike the other SNPs detected in this study, G61E was detected in the patients only; it also has no obvious effect on the level of CYP1B1 enzyme, which ranged between 0.844 ± 0.12 ng/ml for the wild type to 1.028 ± 0.37 ng/ml for homozygous mutant type, but we found that TAC decreased significantly in case of the presence of this SNP, it ran between 2.619 ± 0.45 U/ml in the absence G61E and 0.766 ± 0.20 U/ml in case of G61E is present. Correspondingly, MDA showed a significant increase in case of the presence of this SNP, and it ran between 0.769 ± 0.25 μmol/L in the absence G61E and 1.526 ± 0.08 μmol/L in the presence this SNP [Table 3]. It became clear that G61E is related to high oxidative stress. These findings indicate that G61E does not affect the concentration of CYP1B1 enzyme concentration, but it could affect the enzyme activity, which is in correspondence to the oxidative status representing by TAC and MDA. This is consent with the earlier report by Chavarria-Soley et al. who demonstrated that glycine 61 residue is located at the gate of the substrate entry channel to the active site of the enzyme, and residues in this section of the enzyme structure was shown to affect both steric and in electrostatic entrance of the substrate, thus affecting the enzyme activity without affecting the stability and the abundance of the enzyme.[44] Thus, higher enzymatic concentration does not necessarily mean higher enzymatic activity. The increased concentration of the enzyme could have a genetic cause or it could be a result for environmental factors such as increased oxidative stress caused by endogenous and exogenous sources, which could be an inducer for the elevation in the enzyme concentration.[45],[46]

Other novel SNPs (g.6705G>A, g.6813G>A, g.10068ins10069, g.10138ins10139, and g.10191ins10192) were detected with low distributions both in patients and controls [Table 2], and they need further investigation to discover if they have a role in the pathogenesis of PCG.


   Conclusions Top


This study confirms that CYP1B1g ene has an important role in the pathogenesis of PCG in the Iraqi population. G61E which was detected in patients only and was associated with increased oxidative stress, it is considered as the disease-related allele. While all other detected SNPs (the previously reported SNPs [E229K, D449D] and the novel SNPs [g.6705G>A, g.6813G>A, g.10068ins10069, g.10138ins10139, and g.10191ins10192]) were detected both in patients and controls and have no clear effect on, enzyme concentration or the oxidative status; therefore, they cannot be considered as disease-related alleles.

Acknowledgment

The researchers would like to thank all the children's parents for their approval to participate in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Thylefors B, Négrel AD. The global impact of glaucoma. Bull World Health Organ 1994;72:323-6.  Back to cited text no. 1
    
2.
Faiq M, Mohanty K, Dada R, Dada T. Molecular diagnostics and genetic counseling in primary congenital glaucoma. J Curr Glaucoma Pract 2013;7:25-35.  Back to cited text no. 2
    
3.
Mohanty K, Tanwar M, Dada R, Dada T. Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma. Mol Vis 2013;19:78-84.  Back to cited text no. 3
    
4.
Chakrabarti S, Ghanekar Y, Kaur K, Kaur I, Mandal AK, Rao KN, et al. A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma. Hum Mol Genet 2010;19:4083-90.  Back to cited text no. 4
    
5.
Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma – A distinct phenotype caused by recessive LTBP2 mutations. Mol Vis 2011;17:2570-9.  Back to cited text no. 5
    
6.
Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, et al. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 2009;84:664-71.  Back to cited text no. 6
    
7.
Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye (Lond) 2000;14(Pt3B):422-8.  Back to cited text no. 7
    
8.
Sarfarazi M, Akarsu AN, Hossain A, Turacli ME, Aktan SG, Barsoum-Homsy M, et al. Assignment of a locus (GLC3A) for primary congenital glaucoma (Buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics 1995;30:171-7.  Back to cited text no. 8
    
9.
Firasat S, Riazuddin SA, Khan SN, Riazuddin S. Novel CYP1B1 mutations in consanguineous Pakistani families with primary congenital glaucoma. Mol Vis 2008;14:2002-9.  Back to cited text no. 9
    
10.
Al-Rubae'i SH, Jubair S, Al-Sharifi AN, Al-Moosawi M. Investigation of rs121918356 and rs121918355 LTBP2 Mutations and LTBP2 serum levels in primary congenital glaucoma in a sample of Iraqi children. Jordan J Biol Sci 2019;12:77-6.  Back to cited text no. 10
    
11.
Rauf B, Irum B, Kabir F, Firasat S, Naeem MA, Khan SN, et al. A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent. Hum Genome Var 2016;3:16021.  Back to cited text no. 11
    
12.
Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, Jabak M, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 1998;62:325-33.  Back to cited text no. 12
    
13.
Plásilová M, Stoilov I, Sarfarazi M, Kádasi L, Feráková E, Ferák V. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet 1999;36:290-4.  Back to cited text no. 13
    
14.
Mashima Y, Suzuki Y, Sergeev Y, Ohtake Y, Tanino T, Kimura I, et al. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2001;42:2211-6.  Back to cited text no. 14
    
15.
Ohtake Y, Tanino T, Suzuki Y, Miyata H, Taomoto M, Azuma N, et al. Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma. Br J Ophthalmol 2003;87:302-4.  Back to cited text no. 15
    
16.
Panicker SG, Reddy AB, Mandal AK, Ahmed N, Nagarajaram HA, Hasnain SE, et al. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci 2002;43:1358-66.  Back to cited text no. 16
    
17.
Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R. Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients. Mol Vis 2009;15:1200-9.  Back to cited text no. 17
    
18.
Sheikh SA, Waryah AM, Narsani AK, Shaikh H, Gilal IA, Shah K, et al. Mutational spectrum of the CYP1B1 gene in Pakistani patients with primary congenital glaucoma: Novel variants and genotype-phenotype correlations. Mol Vis 2014;20:991-1001.  Back to cited text no. 18
    
19.
Abu-Amero KK, Osman EA, Mousa A, Wheeler J, Whigham B, Allingham RR, et al. Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: Genotype-phenotype correlation. Mol Vis 2011;17:2911-9.  Back to cited text no. 19
    
20.
Hilal L, Boutayeb S, Serrou A, Refass-Buret L, Shisseh H, Bencherifa F, et al. Screening of CYP1B1 and MYOC in Moroccan families with primary congenital glaucoma: Three novel mutations in CYP1B1. Mol Vis 2010;16:1215-26.  Back to cited text no. 20
    
21.
El-Gayar S, Ganesh A, Chavarria-Soley G, Al-Zuhaibi S, Al-Mjeni R, Raeburn S, et al. Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: A pilot study. Mol Vis 2009;15:1325-31.  Back to cited text no. 21
    
22.
Tang YM, Wo YY, Stewart J, Hawkins AL, Griffin CA, Sutter TR, et al. Isolation and characterization of the human cytochrome P450 CYP1B1 gene. J Biol Chem 1996;271:28324-30.  Back to cited text no. 22
    
23.
Jansson I, Stoilov I, Sarfarazi M, Schenkman JB. Effect of two mutations of human CYP1B1, G61E and R469W, on stability and endogenous steroid substrate metabolism. Pharmacogenetics 2001;11:793-801.  Back to cited text no. 23
    
24.
Shimada T, Gillam EM, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H. Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos 1997;25:617-22.  Back to cited text no. 24
    
25.
Banerjee A, Chakraborty S, Chakraborty A, Chakrabarti S, Ray K. Functional and structural analyses of CYP1B1 variants linked to congenital and adult-onset glaucoma to investigate the molecular basis of these diseases. PLoS One 2016;11:e0156252.  Back to cited text no. 25
    
26.
Chambers D, Wilson L, Maden M, Lumsden A. RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1. Development 2007;134:1369-83.  Back to cited text no. 26
    
27.
Chen H, Howald WN, Juchau MR. Biosynthesis of all-trans-retinoic acid from all-trans-retinol: Catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos 2000;28:315-22.  Back to cited text no. 27
    
28.
Reis LM, Semina EV. Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma. Birth Defects Res C Embryo Today 2015;105:96-113.  Back to cited text no. 28
    
29.
Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 1999;286:487-91.  Back to cited text no. 29
    
30.
Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 2006;6:947-60.  Back to cited text no. 30
    
31.
Faiq MA, Dada R, Qadri R, Dada T. CYP1B1-mediated pathobiology of primary congenital glaucoma. J Curr Glaucoma Pract 2015;9:77-80.  Back to cited text no. 31
    
32.
Doshi M, Marcus C, Bejjani BA, Edward DP. Immunolocalization of CYP1B1 in normal, human, fetal and adult eyes. Exp Eye Res 2006;82:24-32.  Back to cited text no. 32
    
33.
Ferreira SM, Lerner SF, Brunzini R, Evelson PA, Llesuy SF. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol 2004;137:62-9.  Back to cited text no. 33
    
34.
Zhao Y, Sorenson CM, Sheibani N. Cytochrome P450 1B1 and primary congenital glaucoma. J Ophthalmic Vis Res 2015;10:60-7.  Back to cited text no. 34
[PUBMED]  [Full text]  
35.
Tanwar M, Dada T, Sihota R, Dada R. Mitochondrial DNA analysis in primary congenital glaucoma. Mol Vis 2010;16:518-33.  Back to cited text no. 35
    
36.
Kahn MG, Giblin FJ, Epstein DL. Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility. Invest Ophthalmol Vis Sci 1983;24:1283-7.  Back to cited text no. 36
    
37.
Suri F, Yazdani S, Narooie-Nejhad M, Zargar SJ, Paylakhi SH, Zeinali S, et al. Variable expressivity and high penetrance of CYP1B1 mutations associated with primary congenital glaucoma. Ophthalmology 2009;116:2101-9.  Back to cited text no. 37
    
38.
Al-Rubae'i SH, Jubair S, Al-Sharifi AN. The impact of oxidative stress in primary congenital glaucoma. Res J Pharm Technol 2018;11:5013-6.  Back to cited text no. 38
    
39.
Campos-Mollo E, López-Garrido MP, Blanco-Marchite C, Garcia-Feijoo J, Peralta J, Belmonte-Martínez J, et al. CYP1B1 mutations in Spanish patients with primary congenital glaucoma: Phenotypic and functional variability. Mol Vis 2009;15:417-31.  Back to cited text no. 39
    
40.
Chavarria-Soley G, Michels-Rautenstrauss K, Pasutto F, Flikier D, Flikier P, Cirak S, et al. Primary congenital glaucoma and Rieger's anomaly: Extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations. Mol Vis 2006;12:523-31.  Back to cited text no. 40
    
41.
Chitsazian F, Tusi BK, Elahi E, Saroei HA, Sanati MH, Yazdani S, et al. CYP1B1 mutation profile of Iranian primary congenital glaucoma patients and associated haplotypes. J Mol Diagn 2007;9:382-93.  Back to cited text no. 41
    
42.
López-Garrido MP, Sánchez-Sánchez F, López-Martínez F, Aroca-Aguilar JD, Blanco-Marchite C, Coca-Prados M, et al. Heterozygous CYP1B1 gene mutations in Spanish patients with primary open-angle glaucoma. Mol Vis 2006;12:748-55.  Back to cited text no. 42
    
43.
Stoilov IR, Costa VP, Vasconcellos JP, Melo MB, Betinjane AJ, Carani JC, et al. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci 2002;43:1820-7.  Back to cited text no. 43
    
44.
Chavarria-Soley G, Sticht H, Aklillu E, Ingelman-Sundberg M, Pasutto F, Reis A, et al. Mutations in CYP1B1 cause primary congenital glaucoma by reduction of either activity or abundance of the enzyme. Hum Mutat 2008;29:1147-53.  Back to cited text no. 44
    
45.
Verma S, Saxena R, Siddiqui MH, Santha K, Sethupathy S. Evaluation of CYP1B1 expression, oxidative stress and phase 2 detoxification enzyme status in oral squamous cell carcinoma patients. J Clin Diagn Res 2017;11:BC01-5.  Back to cited text no. 45
    
46.
Jubair S, Muftin NQ, Hashim N, Rieyadh S, Saad H. Investigation of MYOC gene involvement in primary congenital glaucoma in a sample of Iraqi children. Gene Reports 2019;16:1-4.  Back to cited text no. 46
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
  
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Methods
   Results
   Discussion
   Conclusions
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed429    
    Printed17    
    Emailed0    
    PDF Downloaded27    
    Comments [Add]    

Recommend this journal