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A Missense Mutation G2320R in the Thyroglobulin Gene Causes Non-goitrous Congenital Primary Hypothyroidism in the WIC-rdw Rat

Division of Endocrinology (P.S.K., S.M., B.L.) Department of Medicine University of Cincinnati and Veterans Affairs Medical Center Cincinnati, Ohio 45267
Graduate Program in Cell and Molecular Biology (P.S.K., S.M.) Department of Cell Biology University of Cincinnati College of Medicine Cincinnati, Ohio 45267
Center for Experimental Animal Science (M.D., C.-G.J., J.-M.C., T.M., T.A.) Nagoya City University Medical School Nagoya, Aichi 467-8601, Japan
Department of Laboratory Animal Science (S.-i.F.) Kitasato University School of Medicine Sagamihara, Kanagawa 228-8555, Japan

A convincing line of evidence is being developed that the congenital nongoitrous hypothyroidism and dwarfism observed in the WIC-rdw rat may indeed be caused by a primary defect in thyroid hormonogenesis. In support of this hypothesis, several recent reports have shown the presence of elevated molecular chaperone levels in the WIC-rdw thyrocytes, the endoplasmic reticulum of which was markedly dilated, suggesting a defect in intracellular protein transport. Here the studies were undertaken to identify the precise molecular defect in the WIC-rdw rat. First, the genetic linkage analysis revealed that the rdw locus was on rat chromosome 7 and was identical to the thyroglobulin (Tg) gene locus. Moreover, the Tg protein level was reduced in the WIC-rdw thyroid despite a similar level of the Tg gene transcripts that were indistinguishable in their size from the normal. Next, the complete sequencing of the rdw and the normal rat Tg cDNAs revealed a single nucleotide change, G6958C, resulting in a G2320R missense mutation in a highly conserved region of the Tg molecule. Finally, transient expression of the intact Tg cDNA containing the rdw mutation in the COS-7 cells showed no detectable Tg in the secreted media, indicating a severe defect in the export of the mutant Tg. Together, our observations suggest that a missense mutation, G2320R, in the Tg gene is responsible for the rdw mutation in the WIC-rdw rat.

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