|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1999 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1998 : ¥1,100,000 (Direct Cost : ¥1,100,000)
In order to investigate if goiter is caused by genetic abnormalities of thyroglobulin (TG), we sequenced the entire TG cDNA from 24 goiter patients with unknown etiology. We identified two missense mutations, 3787T→C and 5983T→A, in patients with congenital goiter and a variant type of adenomatous goiter, respectively. The both mutations caused substitution of cysteine with other amino acids, Cys1263Arg and Cys1995Ser, which resulted in abnormal three dimensional structure of TG due to impaired disulfide bond formation. The mutant TG was retained in the endoplasmic reticulum (ER) as evidenced by sensitivity to endoglycosidase H treatment and formation of high molecular-weight TG aggregates, suggesting that the molecular mechanism is ER storage disease. Expression of molecular chaperones, GRP94, GRP78, ERp72, hsp7O, ERp6O, calreticulin, and protein disulfide isomerase, was increased by the ER stress response mediated by Ire1p or ATF6. We also found 18 single nucleotide polymorphisms in the TG gene, some of which are unique in Japanese and the others are shared between Japanese and Caucasians.
The rdw rat is a strain with congenital dwarfism with low serum GH and prolactin concentrations. Subsequently, it was shown that hypothyroidism is the primary defect of many phenotypic manifestations and hormonal abnormalities of the rdw rat. We analyzed the Tg gene. We first cloned the rat TG cDNA and compared the entire sequence of the rdw rat with that of closely related rat strains. We identified a missense mutation, Gly232OArg, which caused impaired intracellular transport of the mutant TG.