Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism

Eunkuk Park,Masami Murakami,Sihoon Lee,Jeonghyun Kim,Katsuhiko Tsunekawa,Seon-Yong Jeong,Jaehoon Jung,So Young Park,Osamu Araki

doi:10.1038/s41598-018-28480-0

Abstract

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[Ser]Sec) 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.

Highlights

Thyroid hormone metabolism is tightly regulated by the hypothalamic-pituitary-thyroid (HPT) axis through its positive and negative feedback mechanisms
Clinical characteristics of patients with abnormal thyroid hormone metabolism characterized by substantially decreased Deiodinase 2 (DIO2) activity
Generally believed that DIO2 T92A is associated with both an impaired baseline psychological well-being on L-T4 and an variant and heterozygous TSHR R450H mutation (Patient)

Summary

Introduction

Thyroid hormone metabolism is tightly regulated by the hypothalamic-pituitary-thyroid (HPT) axis through its positive and negative feedback mechanisms. Thyroid hormone regulation at the cellular level remains largely unknown except for several important deiodinases (DIOs). Type 2 iodothyronine deiodinase (DIO2) converts inactive (thyroxine, T4) to “active” thyroid hormone (3,5,3′-triiodothyronine, T3) and plays a significant role as a determinant of the final concentration of T3. Questions about the efficacy of L-T4 monotherapy still remain since 10% to 15% of patients complain of residual symptoms of hypothyroidism, including neurocognitive dysfunction, poor well-being and physical deterioration. Recent studies suggest that deiodinase activity may vary from its encoding gene and highlight the possible role for individualized medicine based on DIO single nucleotide polymorphisms (SNPs)[6,7]. This study first describes patients with a novel form of abnormal thyroid hormone metabolism characterized by substantially decreased DIO2 activity. The causal relationship between this combination of genetic alterations and decreased DIO2 activity is described

Methods

Results

Conclusion