Thyroid Hormone Receptor alpha Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice
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Published version
Author(s)
Type
Journal Article
Abstract
A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid
hormone receptor 1 (TR1). Affected children have a high serum T3:T4 ratio and variable degrees
of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an
attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are
receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far.
Thra1PV/ mice express a similar potent dominant-negative mutant TR1 to affected individuals,
and thus represent an excellent disease model.We hypothesized that Thra1PV/ mice could be used
to predict the skeletal outcome of human THRA mutations and determine whether prolonged
treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female
Thra1PV/ mice had short stature, grossly abnormal bone morphology but normal bone
strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect
on skeletalmaturation, linear growth, or bonemineralization, thus demonstrating profound tissue
resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone
stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our
studies establish that TR1 has an essential role in the developing and adult skeleton and predict
that patients with different THRA mutations will display variable responses to T4 treatment, which
depend on the severity of the causative mutation. (Endocri
hormone receptor 1 (TR1). Affected children have a high serum T3:T4 ratio and variable degrees
of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an
attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are
receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far.
Thra1PV/ mice express a similar potent dominant-negative mutant TR1 to affected individuals,
and thus represent an excellent disease model.We hypothesized that Thra1PV/ mice could be used
to predict the skeletal outcome of human THRA mutations and determine whether prolonged
treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female
Thra1PV/ mice had short stature, grossly abnormal bone morphology but normal bone
strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect
on skeletalmaturation, linear growth, or bonemineralization, thus demonstrating profound tissue
resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone
stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our
studies establish that TR1 has an essential role in the developing and adult skeleton and predict
that patients with different THRA mutations will display variable responses to T4 treatment, which
depend on the severity of the causative mutation. (Endocri
Date Issued
2014-06-10
Date Acceptance
2014-04-11
Citation
Endocrinology, 2014, 155 (9), pp.3699-3712
ISSN
1945-7170
Publisher
Endocrine Society
Start Page
3699
End Page
3712
Journal / Book Title
Endocrinology
Volume
155
Issue
9
Copyright Statement
© 2014 The Authors. This article has been published under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the Endocrine Society the exclusive right to publish the article and identify itself as the original publisher.
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Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
LIGAND-BINDING DOMAIN
IODOTHYRONINE DEIODINASE
CLINICAL PHENOTYPE
MINERAL DENSITY
BONE
BETA
GROWTH
OSTEOARTHRITIS
GENE
HYPOTHYROIDISM
Publication Status
Published