The mouse Dio3 gene codes for the type 3 iodothyronine deiodinase (D3), a conserved selenocysteine-containing enzyme that inactivates thyroid hormones and is highly expressed during early development. The mouse Dio3 gene and its human homolog map to chromosomal regions that are known to contain imprinted genes. We assessed the allelic expression of the Dio3 using a mouse model in which the gene had been inactivated by the introduction of a critical mutation in the selenocysteine codon. We compared Dio3 gene expression in fetuses that were either wild type or heterozygous (+/-Dio3) for the mutation. D3 enzymatic activities in the head, limbs, liver and body of heterozygous fetuses (E14 to E18) that inherited the mutation from the mother were no different from those found in their wild type littermates. However, D3 activities in heterozygous animals that inherited the mutation from the father were only 18 to 28% of the activities of their wild type littermates in these same tissues. No detectable activity was found in fetuses homozygous for the mutation indicating full inactivation of the enzyme. Northern analysis of mRNA from E15 fetuses showed that the Dio3 mRNA transcripts generated from the paternal allele were at least 5 times more abundant than the transcripts originated from the maternal allele. We conclude that the Dio3 gene is subject to genomic imprinting and preferentially expressed from the paternal allele in the mouse fetus. We also identified a gene that is transcribed antisense from the Dio3 locus. The Dio3 gene likely belongs to the same cluster of imprinted genes detected in mouse chromosome 12 and human chromosome 14 and should be considered as a candidate gene that might play a role in the phenotypic abnormalities associated with uniparental disomy of those chromosomes, a condition in which gene expression is altered due to abnormal genomic imprinting.

Although thyroid hormones are critically important for the coordination of morphogenic processes in the fetus and neonate, premature exposure of the embryo to levels of the hormones present in the adult is detrimental and can result in growth retardation, malformations, and even death. We report here that the pregnant rat uterus expresses extremely high levels of the type 3 iodothyronine deiodinase (D3), which inactivates thyroxine and 3,3′,5-triiodothyronine by 5-deiodination. Both D3 mRNA and activity were present at the implantation site as early as gestational day 9 (E9), when expression was localized using in situ hybridization to uterine mesometrial and antimesometrial decidual tissue. At later stages of gestation, uterine D3 activity remained very high, and the levels exceeded those observed in the placenta and in fetal tissues. After days E12 and E13, as decidual tissues regressed, D3 expression became localized to the epithelial cells lining the recanalized uterine lumen that surrounds the fetal cavity. These findings strongly suggest that the pregnant uterus, in addition to the placenta, plays a critical role in determining the level of exposure of the fetus to maternal thyroid hormones.J. Clin. Invest. 103:979-987 (1999).

The deiodinase types 2 and 3 (D2, D3), which convert T4 to active and inactive metabolites, respectively, are expressed in the rodent uterus and highly induced during pregnancy. To examine the factors regulating the expression of these enzymes in this tissue, we studied D2 and D3 activity in pregnant rats, in pseudopregnant rats before and after the induction of artificial decidualization, and in ovariectomized rats treated with 17beta-estradiol (E2) and/or progesterone (P). Our results demonstrate that induction of D3 activity begins immediately after implantation and increases markedly over the next 72 h. A similar time course and magnitude of D3 induction is noted in the artificially decidualized uterus in pseudopregnant rats, whereas only minimal increases in activity are observed in the nondecidualized control uterine horns in the same animal. In contrast, D2 activity is not induced by a decidualization stimulus. In spontaneously cycling female rats, both D2 and D3 were observed to be 3- to 8-fold higher in proestrus, compared with diestrus. Furthermore, levels of D2 and D3 activity were greatly increased in ovariectomized rats given E2 and P in various combinations. D2 activity was stimulated primarily by E2, whereas E2 and P acted synergistically to increase D3 activity. These results demonstrate that E2 and P regulate thyroid hormone metabolism in the uterus, and that the implantation process is a potent stimulus for the induction of D3 activity in this organ. Such precise and profound changes in deiodinase expression are likely to play important physiological roles in fetal development and may influence uterine function.

This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI.