CONGENITAL HYPOTHYROID GOITER WITH DEFICIENT THYROGLOBULIN - IDENTIFICATION OF AN ENDOPLASMIC-RETICULUM STORAGE DISEASE WITH INDUCTION OF MOLECULAR CHAPERONES

Recent advances in understanding the molecular pathogenesis of congeni tal hypothyroid goiter in cog/cog mice, have raised important question s concerning the maturation of thyroglobulin (the thyroid prohormone) in certain human kindreds with congenital goiter, We have now examined affected siblings from two unrelated families that synthesize an appa rently normally glycosylated, >300 kD immunoreactive thyroglobulin, ye t have a reduced quantity of intraglandular thyroglobulin and that sec reted into the circulation From thyroid tissues of the four patients, light microscopic approaches demonstrated presence of intracellular th yroglobulin despite its absence in thyroid follicle lumina, while elec tron microscopy indicated abnormal distention of the endoplasmic retic ulum (ER). We have confirmed biochemically that most intrathyroidal th yroglobulin fails to reach the (Golgi) compartment where complex carbo hydrate modification takes place, Moreover, the disease in the affecte d patients is associated with massive induction of specific ER molecul ar chaperones including the hsp90 homolog, GRP94, and the hsp70 homolo g, Bip. The data suggest that these patients synthesize a mutant thyro globulin which is defective for folding/assembly, leading to a markedl y reduced ability to export the protein from the ER. Thus, these kindr eds suffer from a thyroid ER storage disease, a cell biological defect phenotypically indistinguishable from that found in cog/cog mice.