UBIAD1 Mutation Alters a Mitochondrial Prenyltransferase to Cause Schnyder Corneal Dystrophy
| Autor: | Brittany N. Kostiha, Michael Dean, Masakazu Yamada, Richard Grutzmacher, Ke Ping Xu, James Chodosh, Chris Croasdale, Marc Goldberg, Maria Hoeltzenbein, Timo Tervo, Ludger A. Wessjohann, Bert Gold, Fushin X Yu, Howard S. Kruth, Michael L. Nickerson, Wolfgang Brandt, S. Bruce Malkowicz, Da Wen Lu, Jayne S. Weiss, John E. Sutphin, William J. Fredericks |
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| Přispěvatelé: | Silmäklinikka |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular DNA Mutational Analysis Mutant Computational Biology/Comparative Sequence Analysis 312 Clinical medicine Computational Biology/Molecular Dynamics Conserved sequence Cornea TRANSFERASE 0302 clinical medicine Protein structure Mutant protein Amino Acids Peptide sequence Genetics and Genomics/Genetics of Disease Conserved Sequence Genetics and Genomics/Medical Genetics Corneal Dystrophies Hereditary 0303 health sciences Multidisciplinary CHOLESTEROL Mitochondria Transport protein Genetics and Genomics/Gene Function Ophthalmology/Inherited Eye Disorders Protein Transport Biochemistry ESCHERICHIA-COLI CRYSTALLINE DYSTROPHY Medicine TOPOLOGY PREDICTION Research Article Science Cardiovascular Disorders Molecular Sequence Data education Computational Biology/Protein Structure Prediction Biology METABOLISM PROTEIN STRUCTURES 03 medical and health sciences Humans Family Amino Acid Sequence Gene Demography 030304 developmental biology Base Sequence Wild type Proteins BLADDER Dimethylallyltranstransferase Molecular biology GENE Mutation Linear Models 030221 ophthalmology & optometry Mutant Proteins MEMBRANE |
| Zdroj: | PLoS ONE PLoS ONE, Vol 5, Iss 5, p e10760 (2010) |
| Popis: | BackgroundMutations in a novel gene, UBIAD1, were recently found to cause the autosomal dominant eye disease Schnyder corneal dystrophy (SCD). SCD is characterized by an abnormal deposition of cholesterol and phospholipids in the cornea resulting in progressive corneal opacification and visual loss. We characterized lesions in the UBIAD1 gene in new SCD families and examined protein homology, localization, and structure.Methodology/principal findingsWe characterized five novel mutations in the UBIAD1 gene in ten SCD families, including a first SCD family of Native American ethnicity. Examination of protein homology revealed that SCD altered amino acids which were highly conserved across species. Cell lines were established from patients including keratocytes obtained after corneal transplant surgery and lymphoblastoid cell lines from Epstein-Barr virus immortalized peripheral blood mononuclear cells. These were used to determine the subcellular localization of mutant and wild type protein, and to examine cholesterol metabolite ratios. Immunohistochemistry using antibodies specific for UBIAD1 protein in keratocytes revealed that both wild type and N102S protein were localized sub-cellularly to mitochondria. Analysis of cholesterol metabolites in patient cell line extracts showed no significant alteration in the presence of mutant protein indicating a potentially novel function of the UBIAD1 protein in cholesterol biochemistry. Molecular modeling was used to develop a model of human UBIAD1 protein in a membrane and revealed potentially critical roles for amino acids mutated in SCD. Potential primary and secondary substrate binding sites were identified and docking simulations indicated likely substrates including prenyl and phenolic molecules.Conclusions/significanceAccumulating evidence from the SCD familial mutation spectrum, protein homology across species, and molecular modeling suggest that protein function is likely down-regulated by SCD mutations. Mitochondrial UBIAD1 protein appears to have a highly conserved function that, at least in humans, is involved in cholesterol metabolism in a novel manner. |
| Databáze: | OpenAIRE |
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