BACKGROUND: Patients with isolated vitamin E deficiency have an impaired ability to incorporate alpha-tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the alpha-tocopherol-transfer protein, which is presumed to function in the intracellular transport of alpha-tocopherol, is abnormal in these patients. METHODS: 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 micrograms per milliliter [2.8 mumol per liter]). Exons of his gene for the alpha-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 alpha-to-copherol-transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for alpha-tocopherol-transfer activity. RESULTS: The patient was homozygous for a point mutation that replaces histidine (CAT) with glutamine (CAG) at position 101 of the gene for the alpha-tocopherol-transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective alpha-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 micrograms per milliliter [17.4 +/- 5.1 vs. 23.4 +/- 6.5 mumol per liter]; P = 0.002). CONCLUSIONS: alpha-Tocopherol-transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.
BACKGROUND:Patients with isolated vitamin E deficiency have an impaired ability to incorporate alpha-tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the alpha-tocopherol-transfer protein, which is presumed to function in the intracellular transport of alpha-tocopherol, is abnormal in these patients. METHODS: 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 micrograms per milliliter [2.8 mumol per liter]). Exons of his gene for the alpha-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 alpha-to-copherol-transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for alpha-tocopherol-transfer activity. RESULTS: The patient was homozygous for a point mutation that replaces histidine (CAT) with glutamine (CAG) at position 101 of the gene for the alpha-tocopherol-transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective alpha-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 micrograms per milliliter [17.4 +/- 5.1 vs. 23.4 +/- 6.5 mumol per liter]; P = 0.002). CONCLUSIONS:alpha-Tocopherol-transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.
Authors: T Yokota; K Igarashi; T Uchihara; K Jishage; H Tomita; A Inaba; Y Li; M Arita; H Suzuki; H Mizusawa; H Arai Journal: Proc Natl Acad Sci U S A Date: 2001-12-18 Impact factor: 11.205
Authors: R Lodi; R Rinaldi; A Gaddi; S Iotti; R D'Alessandro; N Scoz; M Battino; V Carelli; G Azzimondi; P Zaniol; B Barbiroli Journal: J Neurol Neurosurg Psychiatry Date: 1997-06 Impact factor: 10.154
Authors: L Cavalier; K Ouahchi; H J Kayden; S Di Donato; L Reutenauer; J L Mandel; M Koenig Journal: Am J Hum Genet Date: 1998-02 Impact factor: 11.025