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µ-Crystallin as an Intracellular 3,5,3'-Triiodothyronine Holder in Vivo

Department of Aging Medicine and Geriatrics (S.S., J.-i.M., K.H.), Institute on Aging and Adaptation, Shinshu University, Graduate School of Medicine, and Department of Otorhinolaryngology (N.S., S.U.), Shinshu University School of Medicine, Matsumoto 390-8621, Japan

Address all correspondence and requests for reprints to: Satoru Suzuki, M.D., Ph.D., Department of Aging Medicine and Geriatrics, Institute on Aging and Adaptation, Shinshu University, Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail: soutaro{at}hsp.md.shinshu-u.ac.jp.

Previously, we identified reduced nicotinamide adenine dinucleotide phosphate-dependent cytosolic T₃ binding protein in rat cytosol. Cytosolic T₃-binding protein is identical to µ-crystallin (CRYM). Recently, CRYM mutations were found in patients with nonsyndromic hereditary deafness. Although it has been established that CRYM plays pivotal roles in reserving and transporting T₃ into the nuclei in vitro and has a clinical impact on hearing ability, the precise functions of CRYM remain to be elucidated in vivo. To further investigate the in vivo functions of CRYM gene products, we have generated mice with targeted disruption of the CRYM gene, which abrogates the production of CRYM. CRYM knockout loses the reduced nicotinamide adenine dinucleotide phosphate-dependent T₃ binding activity in the cytosol of the brain, kidney, heart, and liver. At the euthyroid state, knockout significantly suppresses the serum concentration of T₃ and T₄ despite normal growth, heart rate, and hearing ability. The disruption of the gene does not alter the expression of TSHß mRNA in the pituitary gland or glutathione-S-transferase 2 and deiodinase 1 mRNAs in either the liver or kidney. When radiolabeled T₃ is injected intravenously, labeled T₃ rapidly enters into and then escapes from the tissues in CRYM-knockout mice. These data suggest that because of rapid T₃ turnover, disruption of the CRYM gene decreases T₃ concentrations in tissues and serum without alteration of peripheral T₃ action in vivo.

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Ligands:   Thyroid hormone