Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice
Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice
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DOI：
10.1210/en.2013-2156
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Williams, Graham R.
中科院分区：
文献类型：
--
作者：
Bassett, J. H. Duncan;Boyde, Alan;Williams, Graham R.
一种新的遗传性疾病已被确定是由编码甲状腺激素受体α 1（TR α 1）的THRA突变引起的。受影响的儿童有高血清T3：T4比值和不同程度的智力缺陷和便秘，但表现出一贯严重的骨骼发育不良。为了改善发育迟缓和减轻甲状腺功能减退症的症状，患者正在接受不同剂量和持续时间的T-4治疗，但迄今为止的反应不一致。Thra 1（PV/+）小鼠表达与受影响个体相似的有效显性负突变体TR α 1，因此代表了极好的疾病模型。我们假设Thra 1（PV/+）小鼠可用于预测人类THRA突变的骨骼结局，并确定超生理剂量的T-4延长治疗是否可改善骨骼异常。成年雌性Thra 1（PV/+）小鼠身材矮小，骨形态严重异常，但骨强度正常，尽管骨量高。虽然T-4治疗抑制TSH分泌，但对骨骼成熟、线性生长或骨矿化没有影响，因此证明了组织对甲状腺激素的强烈抵抗。尽管如此，长期的T-4治疗异常增加了骨硬度和强度，表明长期的有害后果的潜力。我们的研究证实，TR α 1在发育和成人骨骼中具有重要作用，并预测具有不同THRA突变的患者将对T-4治疗显示不同的反应，这取决于致病突变的严重程度。
A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor alpha 1 (TR alpha 1). 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 T-4 treatment, but responses have been inconsistent so far. Thra1(PV/+) mice express a similar potent dominant-negative mutant TR alpha 1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1(PV/+) mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T-4 ameliorates the skeletal abnormalities. Adult female Thra1(PV/+) mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T-4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T-4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TR alpha 1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T-4 treatment, which depend on the severity of the causative mutation.