Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase.

Abstract

Schnyder corneal dystrophy (SCD) is a rare genetic eye disease characterized by corneal opacification resulted from deposition of excess free cholesterol. UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is an enzyme catalyzing biosynthesis of coenzyme Q10 and vitamin K2. More than 20 UBIAD1 mutations have been found to associate with human SCD. How these mutants contribute to SCD development is not fully understood. Here, we identified HMGCR as a binding partner of UBIAD1 using mass spectrometry. In contrast to the Golgi localization of wild-type UBIAD1, SCD-associated mutants mainly resided in the endoplasmic reticulum (ER) and competed with Insig-1 for HMGCR binding, thereby preventing HMGCR from degradation and increasing cholesterol biosynthesis. The heterozygous Ubiad1 G184R knock-in (Ubiad1G184R/+) mice expressed elevated levels of HMGCR protein in various tissues. The aged Ubiad1G184R/+ mice exhibited corneal opacification and free cholesterol accumulation, phenocopying clinical manifestations of SCD patients. In summary, these results demonstrate that SCD-associated mutations of UBIAD1 impair its ER-to-Golgi transportation and enhance its interaction with HMGCR. The stabilization of HMGCR by UBIAD1 increases cholesterol biosynthesis and eventually causes cholesterol accumulation in the cornea.

• Authors: Shi-You Jiang, Jing-Jie Tang, Xu Xiao, Wei Qi, Suqian Wu, Chao Jiang, Jiaxu Hong, Jianjiang Xu, Bao-Liang Song, Jie Luo
• Journal: PLoS genetics (PLoS Genet) Vol. 15 Issue 7 Pg. e1008289 (07 2019) ISSN: 1553-7404 [Electronic] United States
• PMID: 31323021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• INSIG1 protein, human
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Cholesterol
• HMGCR protein, human
• Hydroxymethylglutaryl CoA Reductases
• Dimethylallyltranstransferase
• UBIAD1 protein, human

Topics

• Animals
• Cholesterol (metabolism)
• Corneal Dystrophies, Hereditary (genetics, metabolism)
• Dimethylallyltranstransferase (genetics, metabolism)
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism)
• Enzyme Stability
• Golgi Apparatus (metabolism)
• HEK293 Cells
• Humans
• Hydroxymethylglutaryl CoA Reductases (chemistry, metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mass Spectrometry
• Membrane Proteins (metabolism)
• Mice
• Mutation