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Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients.

Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R - Mol. Vis. (2009)

Bottom Line: However, on sequencing, we found that 23/50 (46%) harbored the CYPIB1 mutations.Ter@223 was found in 18%, p.R390H in 16%, and p.R368H in 8% of cases.Ter@223 was found to be the most prevalent mutation in our patients while p.R368H was most prevalent in southern India.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, AIIMS, New Delhi, India.

ABSTRACT

Purpose: Mutations in Cytochrome P450 (CYP1B1) are a predominant cause of congenital glaucoma. This study was planned with the aim to identify the mutation profile of CYP1B1 in North Indian primary congenital glaucoma (PCG) patients.

Methods: After ethical clearance, 50 congenital glaucoma patients and 50 ethnically matched controls were recruited in this study. Genomic DNA was isolated from the blood and trabecular meshwork, and CYP1B1 was screened for the six most prevalent mutations (termination at 223 [Ter@223], Gly61Glu, Pro193Leu, Glu229Lys, Arg368His, and Arg390Cys) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). DNA sequencing was done to identify other mutations and for confirmation of RFLP positive samples.

Results: On PCR-RFLP, 21/50 cases (42%) were found positive for one or more of these mutations. However, on sequencing, we found that 23/50 (46%) harbored the CYPIB1 mutations. Ter@223 was found in 18%, p.R390H in 16%, and p.R368H in 8% of cases. Three novel mutations, p.L24R, p.F190L, and p.G329D, were identified by DNA sequencing. Leucine, phenylalanine, and glycine are conserved at the 24th, 190th, and 329th position in the CYP1B1 protein in different species, suggestive of important functions at these loci. Ter@223 was found to be the most prevalent mutation in our patients while p.R368H was most prevalent in southern India. The difference in frequency and mutation profile may be due to the heterogeneous Indian population. Pathogenic CYP1B1 mutations impair anterior chamber development and differentiation by blocking the aqueous outflow and raising intraocular pressure (IOP).

Conclusions: Three novel mutations were identified in this study. Studies of pathogenic sequence variants in CYP1B1 in different populations may contribute to a better understanding of the disease pathogenesis. This may lead to the development of novel therapeutic approaches in the near future.

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Multiple sequence alignment of various members of the cytochrome P450 super-family. Red letters indicate the conserved residues, which cause the congenital glaucoma phenotype when mutated.
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f6: Multiple sequence alignment of various members of the cytochrome P450 super-family. Red letters indicate the conserved residues, which cause the congenital glaucoma phenotype when mutated.

Mentions: The first 49 residues from the NH2-terminal end and the last 16 residues at the COOH-terminal (residues 528–543) in CYP1B1 did not have corresponding equivalent regions in CYP2c9 from where the structure of the human CYP1B1 protein was determined [14]. Leucine is conserved in the CYP1B1 protein among different species (Figure 6). Thus, we can hypothesize that leucine plays an important role in determining the structure and thus function of this protein.


Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients.

Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R - Mol. Vis. (2009)

Multiple sequence alignment of various members of the cytochrome P450 super-family. Red letters indicate the conserved residues, which cause the congenital glaucoma phenotype when mutated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2697458&req=5

f6: Multiple sequence alignment of various members of the cytochrome P450 super-family. Red letters indicate the conserved residues, which cause the congenital glaucoma phenotype when mutated.
Mentions: The first 49 residues from the NH2-terminal end and the last 16 residues at the COOH-terminal (residues 528–543) in CYP1B1 did not have corresponding equivalent regions in CYP2c9 from where the structure of the human CYP1B1 protein was determined [14]. Leucine is conserved in the CYP1B1 protein among different species (Figure 6). Thus, we can hypothesize that leucine plays an important role in determining the structure and thus function of this protein.

Bottom Line: However, on sequencing, we found that 23/50 (46%) harbored the CYPIB1 mutations.Ter@223 was found in 18%, p.R390H in 16%, and p.R368H in 8% of cases.Ter@223 was found to be the most prevalent mutation in our patients while p.R368H was most prevalent in southern India.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, AIIMS, New Delhi, India.

ABSTRACT

Purpose: Mutations in Cytochrome P450 (CYP1B1) are a predominant cause of congenital glaucoma. This study was planned with the aim to identify the mutation profile of CYP1B1 in North Indian primary congenital glaucoma (PCG) patients.

Methods: After ethical clearance, 50 congenital glaucoma patients and 50 ethnically matched controls were recruited in this study. Genomic DNA was isolated from the blood and trabecular meshwork, and CYP1B1 was screened for the six most prevalent mutations (termination at 223 [Ter@223], Gly61Glu, Pro193Leu, Glu229Lys, Arg368His, and Arg390Cys) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). DNA sequencing was done to identify other mutations and for confirmation of RFLP positive samples.

Results: On PCR-RFLP, 21/50 cases (42%) were found positive for one or more of these mutations. However, on sequencing, we found that 23/50 (46%) harbored the CYPIB1 mutations. Ter@223 was found in 18%, p.R390H in 16%, and p.R368H in 8% of cases. Three novel mutations, p.L24R, p.F190L, and p.G329D, were identified by DNA sequencing. Leucine, phenylalanine, and glycine are conserved at the 24th, 190th, and 329th position in the CYP1B1 protein in different species, suggestive of important functions at these loci. Ter@223 was found to be the most prevalent mutation in our patients while p.R368H was most prevalent in southern India. The difference in frequency and mutation profile may be due to the heterogeneous Indian population. Pathogenic CYP1B1 mutations impair anterior chamber development and differentiation by blocking the aqueous outflow and raising intraocular pressure (IOP).

Conclusions: Three novel mutations were identified in this study. Studies of pathogenic sequence variants in CYP1B1 in different populations may contribute to a better understanding of the disease pathogenesis. This may lead to the development of novel therapeutic approaches in the near future.

Show MeSH
Related in: MedlinePlus