Mutation analysis of CRYAA, CRYGC, and CRYGD associated with autosomal dominant congenital cataract in Brazilian families.

PURPOSE: Congenital cataracts are one of the most treatable causes of visual impairment and blindness during infancy. Approximately 50% of all congenital cataract cases may have a genetic cause. Once there is an intimate relationship between crystallin genes and lens transparency, they are excellent candidate genes for inherited cataract. The purpose of this study was to investigate mutations in alphaA-crystallin (CRYAA), gammaC-crystallin (CRYGC), and gammaD-crystallin (CRYGD) in Brazilian families with nuclear and lamellar autosomal dominant congenital cataract. METHODS: Eleven Brazilian families were referred to the Santa Casa de São Paulo Ophthalmology Department. The coding regions and intron/exon boundaries of CRYAA, CRYGC, and CRYGD were amplified by polymerase chain reaction (PCR) and directly sequenced. Mutation screening was performed in the control group by restriction digestion. RESULTS: Two mutations were observed in different families (Family 4 and Family 10), one is a new mutation (Y56X) in CRYGD and the other a previously reported mutation (R12C) in CRYAA that is correlated with a different phenotype. Genetic analysis revealed previously described polymorphisms in CRYAA (D2D) and CRYGD (Y17Y and R95R). A new polymorphism in CRYGC (S119S) was identified only in Family 1. The mutations as well as the new polymorphism were not observed in the control group. CONCLUSIONS: In conclusion, we report a novel nonsense mutation (Y56X) in CRYGD and a previously reported missense mutation (R12C) in CRYAA associated with nuclear cataract in Brazilian families. Both tyrosine in amino acid 56 in CRYGD and arginine in amino acid 12 in CRYAA have been highly conserved throughout evolution in different species. A new polymorphism (S119S) in CRYGC was also observed in one family. The analysis of nine families excluded possible mutations in the crystallin genes, suggesting that other genes could be involved with congenital cataract.

Graves' disease in Brazilian children and adults: lack of genetic association with CTLA-4 +49A>G polymorphism.

BACKGROUND/AIM: In several populations, major histocompatibility complex and CTLA-4 (cytotoxic T lymphocyte antigen-4) gene polymorphisms are related to adult subjects with Graves' disease (GD). Our aim was to study the association of +49A>G polymorphism of the CTLA-4 gene in Brazilian children and adults with GD and its correlation with clinical and laboratory markers of disease severity. METHODS: CTLA-4 +49A>G polymorphism was established by polymerase chain reaction-restriction fragment length polymorphism analysis in 44 children and 72 adults with GD and compared to a stringent control group consisting of octogenarians with no history of thyroid disease; free T4 and T3 levels and T3/T4 ratio, antithyroid antibodies, and Graves' ophthalmopathy were also evaluated according to genotype. RESULTS: No significant difference was found in the frequency of CTLA-4 +49A>G polymorphism among children and adults with GD compared to controls and within groups. There was no significant correlation between the presence of G allele and Graves' ophthalmopathy, gender, age at diagnosis, and biochemical markers of disease severity. CONCLUSION: The frequency of CTLA-4 +49A>G polymorphism is not different in children and adults with GD compared to the normal control population and does not seem to contribute independently to the severity of the clinical presentation of GD.

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.