The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts.

Abstract

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.