THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women.
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.


METHODS
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.
Molecular Endocrinology Group, Department of Medicine, Imperial College London, 10th Floor Commonwealth Building, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Apostolos
A
Gogakos
John G
JG
Logan
Julian A
JA
Waung
J H Duncan
JH
Bassett
Claus C
CC
Glüer
David M
DM
Reid
Dieter
D
Felsenberg
Christian
C
Roux
Richard
R
Eastell
Graham R
GR
Williams
D015502:Absorptiometry, Photon; D000368:Aged; D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D018776:Genes, erbA / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood; D017698:Postmenopause; D011446:Prospective Studies; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D014807:Vitamin D / Q000097:blood; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D010281:Parathyroid Hormone; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D014807:Vitamin D; D000097564:Iodothyronine Deiodinase Type II