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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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Related in: MedlinePlus

Multi sequence alignment of the human CYP1B1 protein with the CYP1A1 protein from different species. Red Underlined amino acids shows the conserved residues in human CYP1B1 and different CYP1A1 protein from different species (when mutated) causing primary congenital glaucoma phenotype. While Red letter shows amino acid conserved in different CYP1A1 protein from different species but not present in human CYP1B1 protein.
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f8: Multi sequence alignment of the human CYP1B1 protein with the CYP1A1 protein from different species. Red Underlined amino acids shows the conserved residues in human CYP1B1 and different CYP1A1 protein from different species (when mutated) causing primary congenital glaucoma phenotype. While Red letter shows amino acid conserved in different CYP1A1 protein from different species but not present in human CYP1B1 protein.

Mentions: This histidine residue lies in the carboxyl terminal of the G helix in the CYP1B1 protein. Replacement of an aromatic, weak basic, amino acid histidine whose charge state depends upon its protonation state with an aliphatic, strong acidic, and negatively charged aspartic acid at this locus. This in turn affects the local charge distribution, and hence the structure of the protein is disturbed. Histidine is conserved at this locus in the CYP1A1 protein from 12 different species (Figure 8) and in the CYP1B1 protein from seven different species (Figure 9) analyzed, suggesting that histidine performs some important functions at this locus. No other known pathogenic mutation was present in the patient (P61), and the PSIC score of this mutation was 2.628, indicating that this change is probably damaging to the protein function. The SIFT score of p.H279D was 0.00 and is predicted to be deleterious for the protein function.


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)

Multi sequence alignment of the human CYP1B1 protein with the CYP1A1 protein from different species. Red Underlined amino acids shows the conserved residues in human CYP1B1 and different CYP1A1 protein from different species (when mutated) causing primary congenital glaucoma phenotype. While Red letter shows amino acid conserved in different CYP1A1 protein from different species but not present in human CYP1B1 protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Multi sequence alignment of the human CYP1B1 protein with the CYP1A1 protein from different species. Red Underlined amino acids shows the conserved residues in human CYP1B1 and different CYP1A1 protein from different species (when mutated) causing primary congenital glaucoma phenotype. While Red letter shows amino acid conserved in different CYP1A1 protein from different species but not present in human CYP1B1 protein.
Mentions: This histidine residue lies in the carboxyl terminal of the G helix in the CYP1B1 protein. Replacement of an aromatic, weak basic, amino acid histidine whose charge state depends upon its protonation state with an aliphatic, strong acidic, and negatively charged aspartic acid at this locus. This in turn affects the local charge distribution, and hence the structure of the protein is disturbed. Histidine is conserved at this locus in the CYP1A1 protein from 12 different species (Figure 8) and in the CYP1B1 protein from seven different species (Figure 9) analyzed, suggesting that histidine performs some important functions at this locus. No other known pathogenic mutation was present in the patient (P61), and the PSIC score of this mutation was 2.628, indicating that this change is probably damaging to the protein function. The SIFT score of p.H279D was 0.00 and is predicted to be deleterious for the protein function.

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