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High Prevalence of T354P Sodium/Iodide Symporter Gene Mutation in Japanese Patients with Iodide Transport Defect Who Have Heterogeneous Clinical Pictures¹

Department of Laboratory Medicine, Kyoto University School of Medicine (S.K., A.M.), Kyoto 606-8507; the Department of Pathology, Kitasato University School of Medicine (Y.S., T.K.), Sagamihara, Kanagawa 228-0829; Ohyama Clinic (Y.O.), Sagamihara, Kanagawa 228-0802; the Department of Pediatrics, Hokkaido University School of Medicine (K.F.), Sapporo 060-0814; the Department of Pediatrics, Teikyo University Ichihara Hospital (H.I.), Ichihara, Chiba 299-0111; the Department of Medicine, Tokyo Women’s Medical College (O.I.), Tokyo 162-0054, Japan; and the Department of Physiology, Ohio State University (S.M.J.), Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Shinji Kosugi, M.D., Ph.D., Department of Laboratory Medicine, Kyoto University School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: kosugi{at}kuhp.kyoto-u.ac.jp

A missense and loss of function mutation of the Na⁺/I^- symporter (NIS) gene, T354P [Thr³⁵⁴Pro (ACACCA)], was found in the homozygous state in two unrelated Japanese patients with iodide transport defect. In this study we have identified the homozygous T354P NIS germline mutation in seven Japanese patients, including one previously reported, from five unrelated families. No other nucleotide changes were found in the coding regions and the exon-intron boundaries of the NIS gene in these seven patients. These results suggest a common prevalence of the T354P mutation in Japanese patients. Although these seven patients have the identical NIS mutation, T354P, marked heterogeneity in clinical pictures, especially concerning goiter and hypothyroidism, were noted among them. Therefore, another factor(s), but not the nature of the NIS mutation, may account for the clinical heterogeneity among patients with the iodide transport defect. We have previously reported that the NIS messenger ribonucleic acid was markedly increased in the thyroid of a patient with the homozygous T354P mutation. In this study we demonstrated that the NIS proteins in the patients’ thyroids were significantly increased (10-fold) by Western blot analysis of integral membrane proteins using an antibody against the C-terminal peptide of the human NIS. Furthermore, we showed by immunohistochemical staining that the T354P mutant NIS proteins were overexpressed in the basal and lateral plasma membranes of patients’ thyrocytes.

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