TY - JOUR
T1 - Thyroid hormone and DNA binding properties of A mutant c-erbAβ receptor associated with generalized thyroid hormone resistance
AU - Usala, Stephen J.
AU - Wondisford, Fredric E.
AU - Watson, Tracey L.
AU - Menke, Jay B.
AU - Weintraub, Bruce D.
PY - 1990/9/14
Y1 - 1990/9/14
N2 - 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-erbAβ thyroid hormone receptor. In the current study, the thyroid hormone and DNA-binding properties of this mutant receptor were determined using c-erbAβ protein synthesized in vitro. Both the wild-type human placental c-erbAβ 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 × 109 M-1 and 2.3 × 1010 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.
AB - 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-erbAβ thyroid hormone receptor. In the current study, the thyroid hormone and DNA-binding properties of this mutant receptor were determined using c-erbAβ protein synthesized in vitro. Both the wild-type human placental c-erbAβ 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 × 109 M-1 and 2.3 × 1010 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.
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U2 - 10.1016/0006-291X(90)91185-U
DO - 10.1016/0006-291X(90)91185-U
M3 - Article
C2 - 2169728
AN - SCOPUS:0025164139
SN - 0006-291X
VL - 171
SP - 575
EP - 580
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -