Physiological and genetic analyses of inbred mouse strains with a type I iodothyronine 5' deiodinase deficiency.

Abstract

Inbred mouse strains differ in their capacity to deiodinate iododioxin and iodothyronines, with strains segregating into high or low activity groups. Metabolism of iododioxin occurs via the type I iodothyronine 5'deiodinase (51DI), one of two enzymes that metabolize thyroxine (T4) to 3,5,3'-triiodothyronine (T3). Recombinant inbred strains derived from crosses between high and low activity strains exhibit segregation characteristic of a single allele difference. Hepatic and renal 5DI mRNA in a high (C57BL/6J) and low (C3H/HeJ) strain paralleled enzyme activity and concentration, in agreement with a recent report. 5DI-deficient mice had twofold higher serum free T4 but normal free T3 and thyrotropin. Brown adipose tissue 51DII was invariant between the two strains. Southern analyses using a 51DI probe identified a restriction fragment length variant that segregated with 51DI activity in 33 of 35 recombinant inbred strains derived from four different pairs of high and low activity parental strains. Recombination frequencies using previously mapped loci allowed assignment of the 5DI gene to mouse chromosome 4 and identified its approximate chromosomal position. We propose the symbol Diol to denote the mouse 51)I gene. Conserved linkage between this segment of mouse chromosome 4 and human HSAlp predicts this location for human Diol. (J. Clin. Invest. 1993. 92:1517-1528

Regulation of Dio2 gene expression by thyroid hormones in normal and type 1 deiodinase-deficient C3H mice

“…Besides the reduced hepatic and renal D1 activity, the most notable features of the C3H mouse are that, when compared with the C57 mouse, the circulating levels of T 4 and rT 3 are elevated, while those of TSH and T 3 are unchanged. It would therefore be anticipated that in C3H mice the higher serum free T 4 concentration would cause a decrease in D2 activity, which was confirmed by twofold lower D2 activity in pituitary and brain (Berry et al 1993). Here, we demonstrated that the D2 mRNA levels are not different between C3H and C57 mice, providing additional evidence that the reduced D2 activity in C3H mice results from an increased rate of substrate-induced enzyme inactivation.…”

“…However, the expression of D2, another T 4 -activating enzyme, has not been entirely assessed in D1-deficient mice. Comparative analysis of D2 activity levels between C3H and C57 mice demonstrated that pituitary and brain D2 activity in C3H mice was about 50% lower than that in C57 animals (Berry et al 1993), which is attributed to the twofold increase in serum T 4 concentration. The D2 mRNA expression has not been evaluated in the C3H mouse.…”

“…The C3H/HeJ (C3H) inbred mouse has an inherited D1-deficiency which results in approximately tenfold reduction in hepatic levels of D1 mRNA and activity when compared with the C57BL/6J (C57) inbred strain, which presents higher Dio1 expression (Berry et al 1993, Schoenmakers et al 1993. In addition to the inherited D1 deficiency, the C3H mouse exhibits a higher susceptibility to chemically induced hepatocarcinogenesis and lower susceptibility to atherosclerotic plaque formation in response to a high-fat diet and larger spleen, when compared with C57 mice (Paigen et al 1987, Buchmann et al 1991, Manning & McDonald 1997.…”

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

“…Whether this means that these mutations are not compatible with life, that they have little or no consequences, or that they result in unexpected phenotypes is unclear. Based on the phenotypes of mice with targeted deletions of D1, D2, or D3, the most severe effects would be expected of mutations in D3 (43)(44)(45). In the last few years, several polymorphisms in deiodinases have been described (17,46,47) (Fig.…”

Role of type 1 and 2 deiodinases in thyroid metabolism (review)

“…В активном центре трех дейодиназ присутствует редкая аминокислота -селеноцистеин [6]. В селено-протеинах кодон UGA кодирует не терминацию трансляции белка, а инсерцию селеноцистеина.…”