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A Mutation in Tpst2 Encoding Tyrosylprotein Sulfotransferase Causes Dwarfism Associated with Hypothyroidism

Laboratory of Experimental Animal Science (N.S., Y.H., A.N., S.O., A.A., T.A.), Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo 060-0818, Japan; and Center for Experimental Animal Science (M.D., J.-M.C., T.M., I.M.), Nagoya City University Medical School, Mizuho-ku, Nagoya 467-8601, Japan

Address all correspondence and requests for reprints to: Prof. Takashi Agui, Laboratory of Experimental Animal Science, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo 060-0818, Japan. E-mail: agui{at}vetmed.hokudai.ac.jp.

The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid hypoplasia related to TSH hyporesponsiveness. Through genetic mapping and complementation experiments, we show that grt is a missense mutation of a highly conserved region of the tyrosylprotein sulfotransferase 2 (Tpst2) gene, encoding one of the two Tpst genes implicated in posttranslational tyrosine O-sulfation. We present evidence that the grt mutation leads to a loss of TPST2 activity, and TPST2 isoform has a high degree of substrate preference for TSH receptor (TSHR). The expression of TPST2 can restore TSH-TSHR-mediated cAMP production in fibroblasts derived from grt mice. Therefore, we propose that the tyrosine sulfation of TSHR by TPST2 is crucial for TSH signaling and resultant thyroid gland function.