Human Type 1 Iodothyronine Deiodinase (Dio1) Mutations Cause Abnormal Thyroid Hormone Metabolism

Background:Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However,DIO1gene defects have not been reported in humans. Methods:Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenicDIO1variants were used forin vitrostudies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured inDio1heterozygous-null mice. Results:We report the novel identification and characterization of two missenseDIO1pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristicin vivoparameters are also present inDio1heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions:We report the identification and characterization of two missenseDIO1pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.