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Identification of four novel cytochrome P4501B1 mutations (p.I94X, p.H279D, p.Q340H, and p.K433K) in primary congenital glaucoma patients.

Tanwar M, Dada T, Sihota R, Dada R - Mol. Vis. (2009)

Bottom Line: Five coding single nucleotide polymorphisms and one intronic single nucleotide polymorphism (rs2617266) were also found.These developments may help in reducing the disease frequency in familial cases.Such studies will be of benefit in the identification of pathogenic mutations in different populations and will enable us to develop simple and rapid diagnostic tests for analyzing such cases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory For Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

ABSTRACT

Purpose: Primary congenital glaucoma (PCG) is an autosomal recessive eye disorder that is postulated to result from developmental defects in the anterior eye segment. Mutations in the cytochrome P4501B1 (CYP1B1) gene are a predominant cause of congenital glaucoma. In this study we identify CYP1B1 mutations in PCG patients.

Methods: Twenty-three unrelated PCG patients and 50 healthy controls were enrolled in the study. CYP1B1 was screened for mutations by PCR and DNA sequencing.

Results: DNA sequencing revealed a total of 15 mutations. Out of these, four (p.I94X, p.H279D, p.Q340H, and p.K433K) were novel mutations and five were known pathogenic mutations. Five coding single nucleotide polymorphisms and one intronic single nucleotide polymorphism (rs2617266) were also found. Truncating mutations (p.I94X and p.R355X) were associated with the most severe disease phenotype. It is possible that patients with two alleles with no catalytic activity may present with a more severe phenotype of the disease compared to patients with one allele (heterozygous). The disease phenotype of patients with CYP1B1 mutations was more severe compared with the clinical phenotype of patients negative for CYP1B1 mutations.

Conclusion: Mutations in CYP1B1 are a major cause for PCG in our patients. Identifying mutations in subjects at risk of developing glaucoma, particularly among relatives of PCG patients, is of clinical significance. These developments may help in reducing the disease frequency in familial cases. Such studies will be of benefit in the identification of pathogenic mutations in different populations and will enable us to develop simple and rapid diagnostic tests for analyzing such cases.

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Amino acid sequence of CYP1B1 protein. A: Wild-type CYP1B1 protein. B: Truncated CYP1B1 protein of 93 amino acids (black arrow shows the position after which frameshift takes place and red letters shows amino acids after frameshift). C: Truncated CYP1B1 protein of 354 amino acids.
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f7: Amino acid sequence of CYP1B1 protein. A: Wild-type CYP1B1 protein. B: Truncated CYP1B1 protein of 93 amino acids (black arrow shows the position after which frameshift takes place and red letters shows amino acids after frameshift). C: Truncated CYP1B1 protein of 354 amino acids.

Mentions: In the isoleucine94stop mutation (p.194X) mutation a truncated protein of 93 amino acids is produced in which only the first 82 amino acids are the same as the wild-type CYP1B1 protein (Figure 7). This truncated protein lacks all functional domains of the CYP1B1 protein and is a nonfunctional protein [6,21,29,30].


Identification of four novel cytochrome P4501B1 mutations (p.I94X, p.H279D, p.Q340H, and p.K433K) in primary congenital glaucoma patients.

Tanwar M, Dada T, Sihota R, Dada R - Mol. Vis. (2009)

Amino acid sequence of CYP1B1 protein. A: Wild-type CYP1B1 protein. B: Truncated CYP1B1 protein of 93 amino acids (black arrow shows the position after which frameshift takes place and red letters shows amino acids after frameshift). C: Truncated CYP1B1 protein of 354 amino acids.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2802296&req=5

f7: Amino acid sequence of CYP1B1 protein. A: Wild-type CYP1B1 protein. B: Truncated CYP1B1 protein of 93 amino acids (black arrow shows the position after which frameshift takes place and red letters shows amino acids after frameshift). C: Truncated CYP1B1 protein of 354 amino acids.
Mentions: In the isoleucine94stop mutation (p.194X) mutation a truncated protein of 93 amino acids is produced in which only the first 82 amino acids are the same as the wild-type CYP1B1 protein (Figure 7). This truncated protein lacks all functional domains of the CYP1B1 protein and is a nonfunctional protein [6,21,29,30].

Bottom Line: Five coding single nucleotide polymorphisms and one intronic single nucleotide polymorphism (rs2617266) were also found.These developments may help in reducing the disease frequency in familial cases.Such studies will be of benefit in the identification of pathogenic mutations in different populations and will enable us to develop simple and rapid diagnostic tests for analyzing such cases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory For Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

ABSTRACT

Purpose: Primary congenital glaucoma (PCG) is an autosomal recessive eye disorder that is postulated to result from developmental defects in the anterior eye segment. Mutations in the cytochrome P4501B1 (CYP1B1) gene are a predominant cause of congenital glaucoma. In this study we identify CYP1B1 mutations in PCG patients.

Methods: Twenty-three unrelated PCG patients and 50 healthy controls were enrolled in the study. CYP1B1 was screened for mutations by PCR and DNA sequencing.

Results: DNA sequencing revealed a total of 15 mutations. Out of these, four (p.I94X, p.H279D, p.Q340H, and p.K433K) were novel mutations and five were known pathogenic mutations. Five coding single nucleotide polymorphisms and one intronic single nucleotide polymorphism (rs2617266) were also found. Truncating mutations (p.I94X and p.R355X) were associated with the most severe disease phenotype. It is possible that patients with two alleles with no catalytic activity may present with a more severe phenotype of the disease compared to patients with one allele (heterozygous). The disease phenotype of patients with CYP1B1 mutations was more severe compared with the clinical phenotype of patients negative for CYP1B1 mutations.

Conclusion: Mutations in CYP1B1 are a major cause for PCG in our patients. Identifying mutations in subjects at risk of developing glaucoma, particularly among relatives of PCG patients, is of clinical significance. These developments may help in reducing the disease frequency in familial cases. Such studies will be of benefit in the identification of pathogenic mutations in different populations and will enable us to develop simple and rapid diagnostic tests for analyzing such cases.

Show MeSH
Related in: MedlinePlus