Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors?
Y Hayashi, RE Weiss, DH Sarne, PM Yen, T Sunthornthepvarakul, C Marcocci, WW Chin and S Refetoff
Department of Medicine, University of Chicago, Illinois 60637, USA.
Resistance to thyroid hormone (RTH), a syndrome characterized by variable
tissue hyposensitivity to thyroid hormone, is linked to mutations in the
thyroid hormone receptor-beta (TR beta) gene. The purpose of this study was
to determine whether the clinical phenotypes of RTH can be translated in
terms of functional impairment of the corresponding mutant TR beta. Data
from 124 subjects with RTH representing 18 different mutant TR beta s,
showed that serum free T4 levels correlated with the degree of T3-binding
impairment of the corresponding TR beta in 12 of these mutant TR beta s
(group I), but not in the remaining 6 (group II). In subjects from both
groups studied in detail by the administration of incremental doses of T3,
the degree of thyrotroph resistance to T3 correlated with the magnitude of
endogenous free T4 elevation at baseline, but did not parallel the
resistance of peripheral tissues. In transfection studies, all group I
mutant TR beta s inhibited positive transactivation by the wild type TR
beta s to a similar degree in the presence of 1 nmol/L T3, whereas group II
mutant TR beta s exerted a weaker inhibition that was not related to their
T3-dependent trans-activation when tested alone. Similar results were
obtained with negatively regulated reporter genes. It is concluded that the
clinical severity of RTH, determined by thyrotroph resistance, can be
predicted from the degree of T3 binding impairment and dominant negative
potency of mutant TR beta s, but the degree of peripheral tissue resistance
and related clinical manifestations is limited by putative genetic or
environmental factors that modulate the effect of thyroid hormone.
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