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

Jubair, Suzanne; Al-Rubae'i, Salwa H.N.; Al-Sharifi, Ali N M; Suleiman, Ahmed AbdulJabbar

doi:10.4103/meajo.meajo_116_19

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Likewise, at position 61, the hinge region, where glycine, which is a neutral amino acid, was substituted by a negatively charged glutamate. This variant (G61E) was identified in many populations, as reported in previous studies ( Afzal et al, 2019 ; El-Ashry, El-Aziz & Bhattacharya, 2007 ; El-Gayar et al, 2009 ; Jubair et al, 2019 ; Stoilov et al, 1998 ). In this study, it has been shown that most of the high-risk missense variations are found in the carboxyl terminal region of the CYP1B1 protein, which is incorporated into several catabolic activities.…”

Section: Discussionsupporting

confidence: 77%

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Shahid

Azfaralariff

Tufail

et al. 2022

PeerJ

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Background Primary congenital glaucoma (PCG) is the most common subtype of glaucoma caused by defects in the cytochrome P450 1B1 (CYP1B1) gene. It is developing among infants in more than 80% of cases who exhibit impairments in the anterior chamber angle and the trabecular meshwork. Thus, a comprehensive in silico approach was performed to evaluate the effect of high-risk deleterious missense variations in the CYP1B1 gene. Material and methods All the information for CYP1B1 missense variants was retrieved from the dbSNP database. Seven different tools, namely: SIFT, PolyPhen-2, PROVEAN, SNAP2, PANTHER, PhD-SNP, and Predict-SNP, were used for functional annotation, and two packages, which were I-Mutant 2.0 and MUpro, were used to predict the effect of the variants on protein stability. A phylogenetic conservation analysis using deleterious variants was performed by the ConSurf server. The 3D structures of the wild-type and mutants were generated using the I-TASSER tool, and a 50 ns molecular dynamic simulation (MDS) was executed using the GROMACS webserver to determine the stability of mutants compared to the native protein. Co-expression, protein-protein interaction (PPI), gene ontology (GO), and pathway analyses were additionally performed for the CYP1B1 in-depth study. Results All the retrieved data from the dbSNP database was subjected to functional, structural, and phylogenetic analysis. From the conducted analyses, a total of 19 high-risk variants (P52L, G61E, G90R, P118L, E173K, D291G, Y349D, G365W, G365R, R368H, R368C, D374N, N423Y, D430E, P442A, R444Q, F445L, R469W, and C470Y) were screened out that were considered to be deleterious to the CYP1B1 gene. The phylogenetic analysis revealed that the majority of the variants occurred in highly conserved regions. The MD simulation analysis exhibited that all mutants’ average root mean square deviation (RMSD) values were higher compared to the wild-type protein, which could potentially cause CYP1B1 protein dysfunction, leading to the severity of the disease. Moreover, it has been discovered that CYP1A1, VCAN, HSD17B1, HSD17B2, and AKR1C3 are highly co-expressed and interact with CYP1B1. Besides, the CYP1B1 protein is primarily involved in the metabolism of xenobiotics, chemical carcinogenesis, the retinal metabolic process, and steroid hormone biosynthesis pathways, demonstrating its multifaceted and important roles. Discussion This is the first comprehensive study that adds essential information to the ongoing efforts to understand the crucial role of genetic signatures in the development of PCG and will be useful for more targeted gene-disease association studies.

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Section: Discussionsupporting

confidence: 77%

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Shahid

Azfaralariff

Tufail

et al. 2022

PeerJ

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“…This complex relationship likely accounts for the phenotypic differences and ARS classifications in patients with mutations in one of the two causative genes. Mutations in the CYP1B1 gene have been found in a single family with ARS [ 17 ], and while a relatively common cause of congenital glaucoma is some populations [ 18 , 19 ], mutations in CYP1B1 appear to be an extremely rare cause of ARS.…”

Section: Axenfeld–rieger Syndromementioning

confidence: 99%

Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants

French¹

2021

IJMS

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Axenfeld–Rieger syndrome (ARS) encompasses a group of developmental disorders that affect the anterior segment of the eye, as well as systemic developmental defects in some patients. Malformation of the ocular anterior segment often leads to secondary glaucoma, while some patients also present with cardiovascular malformations, craniofacial and dental abnormalities and additional periumbilical skin. Genes that encode two transcription factors, FOXC1 and PITX2, account for almost half of known cases, while the genetic lesions in the remaining cases remain unresolved. Given the genetic similarity between zebrafish and humans, as well as robust antisense inhibition and gene editing technologies available for use in these animals, loss of function zebrafish models for ARS have been created and shed light on the mechanism(s) whereby mutations in these two transcription factors cause such a wide array of developmental phenotypes. This review summarizes the published phenotypes in zebrafish foxc1 and pitx2 loss of function models and discusses possible mechanisms that may be used to target pharmaceutical development and therapeutic interventions.

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“…It was also observed in 7% healthy controls. 27 The CYP1B1 gene variation Arg48Glyc depict in this study that C>G (R48G) is a missense mutation and is not associated with disease.…”

Section: Discussionmentioning

confidence: 64%

Investigation of mutational spectrum in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma

Zahid

Khan

Zulfiqar³

et al. 2023

Pak J Med Sci

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Objective: To identify the genetic variants in the CYP1B1 gene associated with Primary Congenital Glaucoma (PCG) and to predict its pathological effect. Method: A descriptive study was conducted in the time period of nine months (September 2021-May 2022) after the ethical approval was taken from The Children Hospital and Institute of Child Health (CH & ICH). Two milliliters of the blood sample from PCG-affected individuals were collected in EDTA vacutainers and genomic DNA was extracted by a phenol-chloroform method. The semi-quantification of extracted DNA was done by agarose gel electrophoresis. PCR amplification was performed by specific primers of CYP1B1 gene then termination sequencing (di-deoxy) was done to detect the genetic variants. Different bioinformatics tools such as BLAST, Ensembl, Clustal Omega, Polyphen and SIFT were used for the further analysis of mutation causing the disease. Results: A total of 85% of patients were bilaterally affected, while 15% were unilaterally affected. Mutation analysis identified five non related known variants. Two missense mutations (c.355 G/T p.A119S and c.685G/A p.E229K) occurred in 94% patients and intragenic SNP occurred in 29% patients along with the 1% somatic (c.693C/A p.F231L) and stop gained mutation (c.840C/A p.C280*). Conclusion: Genetic analysis in the current study showed that 85% of PCG affected patients were due to the CYP1B1 mutation, and disease heterogeneity might be reduced through genetic counseling. doi: https://doi.org/10.12669/pjms.39.2.7081 How to cite this: Zahid T, Khan MU, Zulfiqar A, Jawad F, Saleem A, Khan AR. Investigation of mutational spectrum in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma. Pak J Med Sci. 2023;39(2):---------. doi: https://doi.org/10.12669/pjms.39.2.7081 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Cited by 8 publications

References 25 publications

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants

Investigation of mutational spectrum in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma

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