Patients with isolated vitamin E deficiency have an impaired ability to incorporate ÃŽÂ±-tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the ÃŽÂ±-tocopherol–transfer protein, which is presumed to function in the intracellular transport of ÃŽÂ±-tocopherol, is abnormal in these patients. We studied a patient from an isolated Japanese island who began to have ataxia, dysarthria, and sensory disturbances in the sixth decade of life. His serum vitamin E concentration was low (1.2 μg per milliliter [2.8 μmol per liter]). Exons of his gene for the ÃŽÂ±-tocopherol–transfer protein were analyzed by DNA sequencing. We also screened an additional 801 inhabitants of the island for the mutation. Both the normal and mutant ÃŽÂ±-tocopherol–transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for ÃŽÂ±-tocopherol–transfer activity. The patient was homozygous for a point mutation that replaces histidine (CAT) with glutamine (CAG) at position 101 of the gene for the ÃŽÂ±-tocopherol–transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective ÃŽÂ±-tocopherol–transfer protein with approximately 11 percent of the transfer activity of the wild-type protein. Of the 801 island inhabitants examined, 21 were heterozygous for the His101Gln mutation. In all affected subjects, including the patient, this mutation cosegregated with an intron-sequence polymorphism. The heterozygotes were phenotypically normal and had serum vitamin E concentrations that were on average 25 percent lower than those of normal subjects (mean [±SD], 7.5±2.2 vs. 10.1±2.8 μg per milliliter [17.4±5.1 vs. 23.4±6.5 μmol per liter]; P = 0.002). ÃŽÂ±-Tocopherol–transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.
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