Mutated UBIAD1 in Schnyder Corneal Dystrophy Binds HMGCR and Vitamin K Biosynthesis Is Impaired

Abstract

Purpose: : To determine the effect of a G177E (substitution of a glutamic acid for glycine) UBIAD1 mutation in Schnyder corneal dystrophy (SCD) on the protein active site and tertiary structure. UBIAD1 is mutated in SCD and was recently shown to be a novel vitamin K (MK-4) biosynthetic enzyme but causal mechanisms of the disease remain unclear.

Methods: : Patients were recruited under Institutional Review Board approval of the University of Massachusetts Medical Center in Worcester, Massachusetts and Kresge Eye Institute of Wayne State University, in Detroit, Michigan. Genotyping was performed to identify the causative gene mutation. Molecular modeling and docking simulations were done to determine the effect of the mutation on the protein. Yeast two-hybrid assays were used to identify binding partners related to the disease.

Results: : Six large pedigrees, including four of Swede Finn heritage, were found to have the G177E mutation in UBIAD1 resulting in SCD. Molecular modeling and docking simulations showed the mutation altered the tertiary structure and active site of the protein and predicted reduced catalysis of MK-4. As predicted, mutant enzyme exhibited significantly reduced catalytic activity compared to native protein. Yeast two-hybrid assays identified interactions between UBIAD1 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1/ACAT). HMGCR is critical for cholesterol biosynthesis and the target of statins, cholesterol lowering drugs, and SOAT1 esterifies cholesterol which has been implicated in early stages of atherosclerosis. The UBIAD1-HMGCR interaction was confirmed using immunoprecipitation and co-localization of the proteins.

Conclusions: : This study identified impaired enzyme activity of UBIAD1 due to SCD mutation and novel binding partners that have direct implications for the disease. These data suggest that UBIAD1 is a novel and poorly understood link between vitamin K and cholesterol metabolism, and, as a pharmacologic target, should be investigated for its potential to treat SCD and atherosclerosis.

Keywords: cornea: basic science • cornea: stroma and keratocytes • genetics