Journal Article

Alpha-crystallin mutations alter lens metabolites in mouse models of human cataracts

Bozeman, Stephanie L., Hsu, Fong-Fu, Andley, Usha P., Frankfater, Cheryl

2020

Overview

Cataracts are a major cause of blindness worldwide and commonly occur in individuals over 70 years old. Cataracts can also appear earlier in life due to genetic mutations. The lens proteins, αA- and αB-crystallins, are chaperone proteins that have important roles maintaining protein solubility to prevent cataract formation. Mutations in the CRYAA and CRYAB crystallin genes are associated with autosomal dominant early onset human cataracts. Although studies about the proteomic and genomic changes that occur in cataracts have been reported, metabolomics studies are very limited. Here, we directly investigated cataract metabolism using gas-chromatography-mass spectrometry (GC-MS) to analyze the metabolites in adult Cryaa-R49C and Cryab-R120G knock-in mouse lenses. The most abundant metabolites were myo-inositol, L-(+)-lactic acid, cholesterol, phosphate, glycerol phosphate, palmitic and 9-octadecenoic acids, α-D-mannopyranose, and β-D-glucopyranose. Cryaa-R49C knock-in mouse lenses had a significant decrease in the number of sugars and minor sterols, which occurred in concert with an increase in lactic acid. Cholesterol composition was unchanged. In contrast, Cryab-R120G knock-in lenses exhibited increased total amino acid content including valine, alanine, serine, leucine, isoleucine, glycine, and aspartic acid. Minor sterols, including cholest-7-en-3-ol and glycerol phosphate were decreased. These studies indicate that lenses from Cryaa-R49C and Cryab-R120G knock-in mice, which are models for human cataracts, have unique amino acid and metabolite profiles.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alanine / alpha-Crystallins - genetics / Amino acid composition / Amino acids / Animal models / Animals / Aspartic acid / Biology and Life Sciences / Blindness / Cataract - genetics / Cataract - metabolism / Cataracts / Cholesterol / Chromatography / Crystal structure / Crystallin / Crystalline lens / Crystallinity / Data analysis / Development and progression / Diabetes / Disease Models, Animal / Endocrinology / Gas chromatography / Gene expression / Gene mutation / Genetic aspects / Glycerol / Glycine / Health aspects / Humans / Inositol / Isoleucine / Lactic acid / Lens, Crystalline - metabolism / Lenses / Leucine / Mass spectrometry / Mass spectroscopy / Medicine / Medicine and Health Sciences / Metabolism / Metabolites / Metabolomics / Methods / Mice / Mice, Inbred C57BL / Mutation / NMR / Nuclear magnetic resonance / Physical Sciences / Proteins / Proteomics / Quality control / Research and Analysis Methods / Scientific imaging / Serine / Solubility / Sterols / Sugar / Valine