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Mutations in the UBIAD1 Gene on Chromosome Short Arm 1, Region 36, Cause Schnyder Crystalline Corneal Dystrophy

¹From the Kresge Eye Institute, the ²Departments of Ophthalmology and ⁵Surgery, and the ⁴Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; the ³Section of Experimental Atherosclerosis, National Institutes of Health, Bethesda, Maryland; ⁶Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; the ⁷Department of Ophthalmology, Klinikum Hanau, Hanau, Germany; the ⁸Departments of Human Genetics and ⁹Ophthalmology, Saarland University, Homburg-Saar, Germany; the ¹⁰Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; the ¹¹Department of Molecular Genetics, The Institute of Ophthalmology, University College London, London, United Kingdom; and ¹²Transgenomic, Gaithersburg, Maryland.

PURPOSE. Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed.

METHODS. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5' untranslated region (UTR) exons.

RESULTS. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes).

CONCLUSIONS. Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.