Abnormal properties of thyroglobulin in mice with inherited congenital goiter (cog/cog)

A recessive autosomal mutation (cog) in mice that results in congenital goiter was recently described. Since the mutation has been linked to the thyroglobulin (TG) gene, we have studied the immunological and physical properties of TG in cog/cog mice. +/Cog mice, which are phenotypically normal, were used as controls. In a mouse TG RIA the displacement curve produced by cog/cog thyroid extract was not parallel to normal murine TG, and at maximum displacement 15.4% of the tracer was still bound to the antibody. Extract from +/cog thyroid tissue produced parallel and complete displacement. Sucrose density gradient velocity centrifugation followed by RIA was used to determine the sedimentation properties of cog/cog TG. An abnormal pattern was obtained; a small peak in the 3-8S area and a broad, poorly defined peak at 12S and extending to above 27S were present. By comparison, +/cog thyroids had sharp peaks at 19S and 27S. These findings suggest that normal TG contains some immunological determinants that are absent, and some that are altered, in cog/cog TG. They also indicate that the association of 12S subunits to form 19S TG in cog/cog mice is weak and abnormal. Thyroid tissue was labeled with Na125I in vivo and with [35S] methionine in vitro. In cog/cog mice iodine was incorporated predominantly into albumin and other non-TG proteins. However, by polyacrylamide gradient gel electrophoresis, distinct 125I-labeled bands comigrating with normal TG were present. The bands migrating with TG were also precipitable with anti-TG antiserum. In +/cog mice TG was the predominant iodinated molecule. With [35S]methionine labeling, cog/cog and +/cog thyroids formed TG with the same electrophoretic mobilities. These data indicate the cog/cog thyroids synthesize TG of normal, or very nearly normal, size. The immunological and sedimentation properties of this TG are abnormal, supporting the possibility that the cog mutation is in the TG gene.