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Editors Selection IGR 12-4

Genetics: Regulatory variants of the CYP1B1 gene in PCG

Comment by Michael Hauser on:

27349 A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma, Chakrabarti S; Ghanekar Y; Kaur K et al., Human Molecular Genetics, 2010; 19: 4083-4090

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In this excellent piece of work, Chakrabarti et al. (1777) demonstrate that 'simple Mendelian' disease is often more complex than expected. A substantial fraction of primary congenital glaucoma (PCG) is caused by highly penetrant, non-synonymous coding mutations in CYP1B1. This paper describes the sequencing of the promoter region of the CYP1B1 gene to explore the role of regulatory variants in the etiology of PCG. Not only do the authors identify a promoter variant (rs2567206) that is strongly associated with PCG, but they also extend this finding to greatly improve our understanding of this disease. First, they conduct genotype/phenotype correlations using ANOVA to model the effects on IOP of the promoter and coding variants. Both sets of variants act independently, but they also interact with one another synergistically to raise IOP. Second, the authors use these observations to predict patient response to surgical treatment. Third, they conduct functional testing of the promoter variant in trabecular meshwork cultures, demonstrating that it reduces transcriptional activity by approximately 90%.

There is 'need for functional studies of associated polymorphisms in order to demonstrate that given variants actually play a causative role'

This work beautifully demonstrates the need for functional studies of associated polymorphisms in order to demonstrate that given variants actually play a causative role, and are not simply associated with disease status through linkage disequilibrium with other functional variants. Fourth, this work makes significant progress in resolving the mechanism of CYP1B1 in causing PCG ‐ this work supports a loss of function model, rather than a gain of function, as has been previously suggested (Vasilou V, Gonzalez FJ. Annu Rev Pharmacol Toxicol 2008; 48: 333-358). This paper represents a blueprint for the thorough mutational analysis of causative genes, highlighting the need for analysis of regulatory as well as coding regions, and demonstrating the tremendous power of functional assays in clarifying the mechanism of disease.

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