Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal Thyroid Hormone Metabolism
- Resource Type
- Authors
- Antonio C. Bianco; Alina German; Samuel Refetoff; Xiao Hui Liao; Gustavo W. Fernandes; Monica M. França; Alexandra M. Dumitrescu
- Source
- Thyroid. 31:202-207
- Subject
- medicine.medical_specialty
Mutation
medicine.diagnostic_test
Endocrinology, Diabetes and Metabolism
Thyroid disease
Thyroid
030209 endocrinology & metabolism
Biology
medicine.disease_cause
medicine.disease
Thyroid function tests
Reverse triiodothyronine
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Internal medicine
Iodothyronine deiodinase
medicine
Missense mutation
Hormone
- Language
- ISSN
- 1557-9077
1050-7256
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, DIO1 gene 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 pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic 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 characteristic in vivo parameters are also present in Dio1 heterozygous-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 missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.