Thyroid hormone and DNA binding properties of a mutant c-erbA beta receptor associated with generalized thyroid hormone resistance.
We have previously reported a family, Kindred A, with autosomal dominant generalized thyroid hormone resistance in which affected members were found to have a mutation in the carboxy-terminal domain of the c-erbA beta thyroid hormone receptor. In the current study, the thyroid hormone and DNA-binding properties of this mutant receptor were determined using c-erbA beta protein synthesized in vitro. Both the wild-type human placental c-erbA beta and Kindred A receptors bound [125I]-triiodothyronine, although the Kindred A receptor had decreased affinity for the hormone. The affinity for triiodothyronine was 4.5 x 10(9) M-1 and 2.3 x 10(10) M-1 for the mutant and wild-type receptors, respectively. No abnormality of DNA-binding was detected with the Kindred A receptor using a sensitive avidin-biotin DNA-binding assay with DNA fragments containing thyroid hormone response elements. The Kindred A mutant receptor which displays abnormal triiodothyronine-binding but normal DNA-binding activities in vitro acts as a dominant negative inhibitor of thyroid hormone action in man.
Usala
S J
SJ
Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
Wondisford
F E
FE
Watson
T L
TL
Menke
J B
JB
Weintraub
B D
BD
D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D013006:Growth Hormone / Q000235:genetics; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013972:Thyrotropin / Q000235:genetics
D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D013972:Thyrotropin; D013006:Growth Hormone; D004247:DNA