A causal gene and proteins related to rdw symptoms in the rdw rat with hereditary dwarfism/hypothyroidism

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The rdw rat was initially isolated as a hereditary dwarf strain from a closed colony of Wistar-Imamichi rat. Marked hypothyroidism was subsequently noted in the rdw rat. Several recent reports have shown the presence of elevated molecular chapelone levels in the 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 and the usefulness for animal models in the 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 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 rdw rat. Furthermore, the usefulness as animal models was indicated in many studies on the rdw rat.