Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
Sci Rep. 2018 Jul 4;8(1):10090. doi: 10.1038/s41598-018-28480-0.
Deiodinase 2 (DIO2) plays an important role in thyroid hormone metabolism and its regulation. However, molecular mechanism that regulates DIO2 activity remains unclear; only mutaions in selenocysteine insertion sequence binding protein 2 and selenocysteine tranfer RNA (tRNA) are reported to result in decreased DIO2 activity. Two patients with clinical evidence of abnormal thyroid hormone metabolism were identified and found to have TSHR mutations as well as DIO2 T92A single nucleotide polymorphism (SNP). Primary-cultured fibroblasts from one patient present a high level of basal DIO2 enzymatic activity, possibly due to compensation by augmented DIO2 expression. However, this high enzymatic active state yet fails to respond to accelerating TSH. Consequently, TSHR mutations along with DIO2 T92A SNP ("double hit") may lead to a significant reduction in DIO2 activity stimulated by TSH, and thereby may have clinical relevance in a select population of hypothyroidism patients who might benefit from a T3/T4 combination therapy.
脱碘酶 2（DIO2）在甲状腺激素代谢及其调节中发挥重要作用。然而，调节 DIO2 活性的分子机制尚不清楚；仅报道了硒代半胱氨酸插入序列结合蛋白 2 和硒代半胱氨酸 tRNA（tRNA）的突变会导致 DIO2 活性降低。发现有两名具有甲状腺激素代谢异常临床证据的患者存在 TSHR 突变以及 DIO2 T92A 单核苷酸多态性（SNP）。一名患者的原代培养成纤维细胞表现出高水平的基础 DIO2 酶活性，这可能是由于 DIO2 表达增强而代偿所致。然而，这种高酶活性状态仍然不能对加速 TSH 做出反应。因此，TSHR 突变与 DIO2 T92A SNP（“双重打击”）可能导致 TSH 刺激的 DIO2 活性显著降低，这在某些甲状腺功能减退症患者中可能具有临床意义，这些患者可能受益于 T3/T4 联合治疗。
