Objective: A new autosomal dominant disorder due to mutation of THRA, which encodes thyroid hormone receptor α, is characterised by severely delayed skeletal development but only slightly abnormal thyroid status. Adult mice with disrupted thyroid hormone action in bone due to a mutation of Thra or deletion of Dio2, encoding the type 2 deiodinase, have high bone mass and mineralisation despite essentially euthyroid status. No individuals with DIO2 mutations have been described and the adult phenotype of patients with THRA mutations is largely unknown. We hypothesised that screening euthyroid adults with high bone mineral density (BMD) could be used to identify individuals with mutations of THRA or DIO2.
Design: The Osteoporosis and Ultrasound Study (OPUS) is a 6-year prospective study of fracture-related factors from five European centres.
Methods: A cohort of 100 healthy euthyroid post-menopausal women with the highest BMD was selected from the OPUS population. We sequenced the intron-exon boundaries and critical exons of THRA and DIO2 in these subjects. TSH, free 3,5,3'-l-triiodothyronine, free thyroxine, vitamin D, parathyroid hormone and bone turnover marker concentrations, and BMD measurements were available in all OPUS participants.
Results: No coding sequence or splice site mutations affecting THRA or DIO2 were identified.
Conclusions: Mutations affecting THRA or DIO2 are not a common cause of high BMD in healthy euthyroid post-menopausal women.