FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 333:1313-1319 November 16, 1995 Number 20 Next

Adult-Onset Spinocerebellar Dysfunction Caused by a Mutation in the Gene for the -Tocopherol–Transfer Protein

	Full Text PDF Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Patients with isolated vitamin E deficiency have an impaired ability to incorporate -tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the -tocopherol–transfer protein, which is presumed to function in the intracellular transport of -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 µg per milliliter [2.8 µmol per liter]). Exons of his gene for the -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 -tocopherol–transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for -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 -tocopherol–transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective -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).

Conclusions -Tocopherol–transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.

Source Information

From the Third Department of Internal Medicine (T.G., Y.Y., N.Y.) and the Department of Health Chemistry (M.A., H.A., K.I.), Faculty of Pharmaceutical Sciences, University of Tokyo; the Department of Neurology, Faculty of Medicine, Tokyo Medical and Dental University (T.Y.); and the Second Department of Internal Medicine, Faculty of Medicine, Nippon Medical School (Y.F.) — all in Tokyo, Japan.

Address reprint requests to Dr. Yamada at the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113, Japan.

Full Text of this Article

Related Letters:

Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the -Tocopherol–Transfer Protein
Yokota T., Shiojiri T., Gotoda T., Arai H.
Extract | Full Text  
N Engl J Med 1996; 335:1770-1771, Dec 5, 1996. Correspondence

This article has been cited by other articles:

• Morley, S., Cecchini, M., Zhang, W., Virgulti, A., Noy, N., Atkinson, J., Manor, D. (2008). Mechanisms of Ligand Transfer by the Hepatic Tocopherol Transfer Protein. J. Biol. Chem. 283: 17797-17804 [Abstract] [Full Text]  
• Tanito, M., Yoshida, Y., Kaidzu, S., Chen, Z.-H., Cynshi, O., Jishage, K.-i., Niki, E., Ohira, A. (2007). Acceleration of Age-Related Changes in the Retina in {alpha}-Tocopherol Transfer Protein Null Mice Fed a Vitamin E-Deficient Diet. IOVS 48: 396-404 [Abstract] [Full Text]  
• Tan, P. H., Sagoo, P., Chan, C., Yates, J. B., Campbell, J., Beutelspacher, S. C., Foxwell, B. M. J., Lombardi, G., George, A. J. T. (2005). Inhibition of NF-{kappa}B and Oxidative Pathways in Human Dendritic Cells by Antioxidative Vitamins Generates Regulatory T Cells. J. Immunol. 174: 7633-7644 [Abstract] [Full Text]  
• Min, K. C., Kovall, R. A., Hendrickson, W. A. (2003). Crystal structure of human {alpha}-tocopherol transfer protein bound to its ligand: Implications for ataxia with vitamin E deficiency. Proc. Natl. Acad. Sci. USA 100: 14713-14718 [Abstract] [Full Text]  
• Brigelius-Flohe, R., Kelly, F. J, Salonen, J. T, Neuzil, J., Zingg, J.-M., Azzi, A. (2002). The European perspective on vitamin E: current knowledge and future research. Am. J. Clin. Nutr. 76: 703-716 [Abstract] [Full Text]  
• Feki, M., Belal, S., Feki, H., Souissi, M., Frih-Ayed, M., Kaabachi, N., Hentati, F., Ben Hamida, M., Mebazaa, A. (2002). Serum Vitamin E and Lipid-adjusted Vitamin E Assessment in Friedreich Ataxia Phenotype Patients and Unaffected Family Members. Clin. Chem. 48: 577-579 [Full Text]  
• Yokota, T., Igarashi, K., Uchihara, T., Jishage, K.-i., Tomita, H., Inaba, A., Li, Y., Arita, M., Suzuki, H., Mizusawa, H., Arai, H. (2001). From the Cover: Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: Model for neuronal degeneration caused by chronic oxidative stress. Proc. Natl. Acad. Sci. USA 98: 15185-15190 [Abstract] [Full Text]  
• RICCIARELLI, R., ZINGG, J.-M., AZZI, A. (2001). Vitamin E: protective role of a Janus molecule. FASEB J. 15: 2314-2325 [Abstract] [Full Text]  
• Schuelke, M., Elsner, A., Finckh, B., Kohlschütter, A., Hübner, C., Brigelius-Flohé, R. (2000). Urinary {alpha}-tocopherol metabolites in {alpha}-tocopherol transfer protein-deficient patients. J. Lipid Res. 41: 1543-1551 [Abstract] [Full Text]  
• Usuki, F., Maruyama, K. (2000). Ataxia caused by mutations in the alpha -tocopherol transfer protein gene. J. Neurol. Neurosurg. Psychiatry 69: 254-256 [Abstract] [Full Text]  
• Yokota, T, Uchihara, T, Kumagai, J, Shiojiri, T, Pang, J J, Arita, M, Arai, H, Hayashi, M, Kiyosawa, M, Okeda, R, Mizusawa, H (2000). Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha -tocopherol transfer protein gene. J. Neurol. Neurosurg. Psychiatry 68: 521-525 [Abstract] [Full Text]  
• BRIGELIUS-FLOHÉ, R., TRABER, M. G. (1999). Vitamin E: function and metabolism. FASEB J. 13: 1145-1155 [Abstract] [Full Text]  
• Bogardus, S. T. Jr, Concato, J., Feinstein, A. R. (1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA 281: 1919-1926 [Abstract] [Full Text]  
• Shaw, H.-M., Huang, C.-j. (1998). Liver alpha -Tocopherol Transfer Protein and Its mRNA Are Differentially Altered by Dietary Vitamin E Deficiency and Protein Insufficiency in Rats. J. Nutr. 128: 2348-2354 [Abstract] [Full Text]  
• Castellani, R. (1998). Multiple System Atrophy : Clues from Inclusions. Am. J. Pathol. 153: 671-676 [Full Text]  
• Sun, L., Ishibashi, S., Osuga, J.-i., Harada, K., Ohashi, K., Gotoda, T., Fukuo, Y., Yazaki, Y., Yamada, N. (1998). Clinical Features Associated With the Homozygous Trp64Arg Mutation of the ß3-Adrenergic Receptor : No Evidence for Its Association With Obesity in Japanese. Arterioscler. Thromb. Vasc. Bio. 18: 941-946 [Abstract] [Full Text]  
• Hammans, S R, Kennedy, C R (1998). Ataxia with isolated vitamin E deficiency presenting as mutation negative Friedreich's ataxia. J. Neurol. Neurosurg. Psychiatry 64: 368-370 [Abstract] [Full Text]  
• Arita, M., Nomura, K., Arai, H., Inoue, K. (1997). alpha -Tocopherol transfer protein stimulates the secretion of alpha -tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway. Proc. Natl. Acad. Sci. USA 94: 12437-12441 [Abstract] [Full Text]  
• Yokota, T., Shiojiri, T., Gotoda, T., Arai, H. (1996). Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the {alpha}-Tocopherol-Transfer Protein. NEJM 335: 1770-1771 [Full Text]  
• Rosenberg, R. N. (1996). DNA-Triplet Repeats and Neurologic Disease. NEJM 335: 1222-1224 [Full Text]  
• Rosenberg, R. N. (1995). Spinocerebellar Ataxias and Ataxins. NEJM 333: 1351-1353 [Full Text]