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Molecular genetics of primary congenital glaucoma in Brazil
Ivaylo R Stoilov1, Vital P Costa, Jose P C Vasconcellos
1Molecular Ophthalmic Genetics Laboratory, Surgical Research Center, Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut CT 06030-1110, USA.
Insights
Genetic mutations in the CYP1B1 gene are found in half of Brazilian primary congenital glaucoma (PCG) patients. A specific single nucleotide polymorphism (SNP) haplotype, 5'-C-C-G-G-T-A-3', is linked to most CYP1B1 mutations in PCG.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Primary congenital glaucoma (PCG) is a severe inherited eye disease.
- Genetic factors play a significant role in PCG etiology.
- Understanding the genetic basis of PCG is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the prevalence and spectrum of CYP1B1 gene mutations in Brazilian patients diagnosed with PCG.
- To identify novel mutations and common genetic variations associated with PCG in this population.
Main Methods:
- PCG diagnosis was confirmed based on clinical signs including buphthalmos and elevated intraocular pressure before age three.
- CYP1B1 gene mutation screening was performed on 52 PCG patients using Single-Strand Conformation Polymorphism (SSCP) and direct sequencing.
- Analysis of six intragenic single nucleotide polymorphisms (SNPs) was conducted to determine common haplotypes.
Main Results:
- Mutations in the CYP1B1 gene were identified in 50% of the studied Brazilian PCG patients, with eleven distinct mutations found, including four novel ones.
- A new frameshift mutation (4340delG) was detected in 20.2% of individuals, associated with early-onset, bilateral glaucoma requiring multiple surgeries.
- The SNP haplotype 5 omino-C-C-G-G-T-A-3 omino was the most prevalent among affected Brazilian individuals and was associated with the majority of CYP1B1 mutations.
Conclusions:
- CYP1B1 gene mutations are a significant cause of PCG in the Brazilian population, accounting for approximately half of the cases.
- The 5 omino-C-C-G-G-T-A-3 omino haplotype, containing the high-activity V432 allele, is strongly associated with CYP1B1 mutations in Brazilian PCG patients.
- This haplotype may represent a susceptibility factor for PCG in this population, warranting further investigation.
Purpose:
To determine the distribution of CYP1B1 gene mutations in Brazilian patients with primary congenital glaucoma (PCG).
Methods:
PCG diagnosis was established by presence of buphthalmos in at least one affected eye and associated high intraocular pressures before the age of 3 years. CYP1B1 mutation screening of 52 patients with PCG was performed by SSCP and direct sequencing of PCR fragments.
Results:
Eleven mutations, four of which are novel, were observed in 26 (50%) individuals. A new frameshift mutation (4340delG) was observed in 20.2% of all individuals screened. These individuals had early-onset, bilateral glaucoma that necessitated multiple surgical interventions. CYP1B1 mutations were twice as frequent in affected individuals of European descent as in individuals of African descent. Analysis of six intragenic single nucleotide polymorphisms (SNPs) established 5'-C-C-G-G-T-A-3' as the most common haplotype among the affected Brazilian individuals. A nonsense mutation (W57X) previously reported in an individual with Peters anomaly (compound heterozygote) was also observed in two individuals with PCG but combined with different mutations. A newly developed SSCP assay enabled us to detect all DNA mutations and polymorphisms previously detected by direct sequencing.
Conclusions:
Our results indicate that CYP1B1 mutations may be responsible for half of cases of PCG in the Brazilian population. The SNP haplotype 5'-C-C-G-G-T-A-3' was associated with the majority of CYP1B1 mutations. This haplotype harbors the high-activity V432 allele, which is emerging as a putative susceptibility factor in several cancers.