The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts
The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts
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DOI：
10.1210/en.2002-220800
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发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
St Germain, D
中科院分区：
文献类型：
--
作者：
Hernandez, A;Fiering, S;St Germain, D
小鼠dio3基因编码3型碘甲状腺原氨酸脱碘酶(D3)，这是一种保守的含硒半胱氨酸酶，可使甲状腺激素失活，在发育早期高度表达。小鼠的dio3基因和它的人类同源基因映射到已知包含印记基因的染色体区域。我们使用小鼠模型评估了Dio3的等位基因表达，在小鼠模型中，该基因通过引入硒半胱氨酸密码子的关键突变而失活。我们比较了突变为野生型和杂合型(+/-dio3)的胎儿中dio3基因的表达。从母亲那里遗传该突变的杂合子胎儿(E14~E18)的头部、四肢、肝脏和身体中的D3酶活性与其野生型后代中的D3酶活性没有差异。然而，从父亲那里遗传突变的杂合子动物的D3活性仅为其野生型后代在这些组织中的活性的18%至28%。在突变纯合子的胎儿中没有检测到活性，表明该酶完全失活。对E15胎儿的mRNA进行Northern分析表明，来自父亲等位基因的dio3mRNA转录本至少是来自母亲等位基因的转录本的5倍。我们的结论是，dio3基因在小鼠胚胎中受到基因组印记的影响，并从父亲的等位基因中优先表达。我们还鉴定了一个从dio3基因座转录的反义基因。Dio3基因可能属于在小鼠12号染色体和人类14号染色体中检测到的相同的印记基因簇，应该被认为是一个候选基因，可能在这些染色体的单亲二体相关的表型异常中发挥作用，即由于基因组印记异常而导致基因表达改变的情况。
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.