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-Tocopherol transfer protein gene: Exon skipping of all transcripts causes ataxia

From the Department of Medical Genetics (Drs. Tamaru, Hirano, and Ueno), Nara Medical University, Kashihara, Nara; the Department of Neurology(Drs. Tamaru, Kusaka, Ito, and Imai), Kitano Hospital and Neurological Center, Kamiyama, Kita-Ku, Osaka; and the Department of Neurology (Dr. Hirano), Osaka University Medical School, Suita, Osaka, Japan.

Address correspondence and reprint requests to Dr. S. Ueno, Department of Medical Genetics, Nara Medical University, Shijo-cho, 840, Kashihara, Nara 634, Japan.

This report concerns the characterization of the -tocopherol transfer protein (-TTP) gene in a Japanese family affected by ataxia with isolated vitamin E deficiency (AVED). The sequence analysis revealed a G-to-A transition at the 3' end of exon 3 in both alleles, which predicts outsplicing of this exon from premessenger RNA and the concomitant frame shift in the ataxic patient. We used reverse transcriptase-polymerase chain reaction to analyze -TTP gene transcripts. All transcripts in peripheral blood lymphocytes of the AVED patient, who was treated with large doses of vitamin E, lacked exon 3. The deduced truncated protein shares only 43% of the normal -TTP. Normal control tissues and cells contained normal transcripts and, unexpectedly, also the same mutant transcripts as those of the patient, although with different transcription levels. Treatment of normal fibroblasts with clinically relevant concentrations of vitamin E increased production of transcripts in a dose-dependent manner. We propose that exon skipping of all transcripts through the complete inactivation of the splice site accounts for the clinical onset of AVED and for the clinical resistance to vitamin E in our patient.

Supported by a Nakajima Memorial Research Grant (to SU) and by a Nara Medical University Research Grant.

Received October 16, 1996. Accepted in final form February 10, 1997.

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