title: A missense mutation G2320R in the thyroglobulin gene causes non-goitrous congenital primary hypothyroidism in the WIC-rdw rat.
abstract: 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.
authors: Department of Medicine, University of Cincinnati and Veterans Affairs Medical Center, Ohio 45267, USA.
authors: P S
authors: PS
authors: Kim
authors: M
authors: M
authors: Ding
authors: S
authors: S
authors: Menon
authors: C G
authors: CG
authors: Jung
authors: J M
authors: JM
authors: Cheng
authors: T
authors: T
authors: Miyamoto
authors: B
authors: B
authors: Li
authors: S
authors: S
authors: Furudate
authors: T
authors: T
authors: Agui
mesh_terms: D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003409:Congenital Hypothyroidism; D018076:DNA, Complementary; D004392:Dwarfism / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006042:Goiter / Q000378:metabolism; D007037:Hypothyroidism / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D013954:Thyroglobulin / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D013954:Thyroglobulin