Forrest D, Erway L C, Ng L, Altschuler R, Curran T
Mount Sinai School of Medicine, Department of Human Genetics, New York, New York 10029, USA.
Nat Genet. 1996 Jul;13(3):354-7. doi: 10.1038/ng0796-354.
Congenital thyroid disorders are often associated with profound deafness, indicating a requirement for thyroid hormone (T3) and its receptors in the development of hearing. Two T3 receptor genes, Tr alpha and Tr beta are differentially expressed, although in overlapping patterns, during development. Thus, the extent to which they mediate unique or redundant functions is unclear. We demonstrate that Tr beta-deficient (Thrb-/-) mice exhibit a permanent deficit in auditory function across a wide range of frequencies, although they show no other overt neurological defects. The auditory-evoked brainstem response (ABR) in Thrb-/- mice, although greatly diminished, displayed normal waveforms, which suggested that the primary defect resides in the cochlea. Although hypothyroidism causes cochlear malformation, there was no evidence of this in Thrb-/- mice. These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea. Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone (RTH), which is typically associated with dominant mutations in Tr beta. However, deafness is generally absent in RTH, indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system. Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions.
先天性甲状腺疾病常与严重耳聋相关，这表明在听力发育过程中需要甲状腺激素（T3）及其受体。在发育过程中，两个T3受体基因Trα和Trβ以重叠模式差异表达。因此，它们介导独特功能或冗余功能的程度尚不清楚。我们证明，Trβ缺陷（Thrb-/-）小鼠在广泛的频率范围内表现出永久性听觉功能缺陷，尽管它们没有其他明显的神经缺陷。Thrb-/-小鼠的听觉脑干反应（ABR）虽然大大减弱，但波形正常，这表明主要缺陷位于耳蜗。虽然甲状腺功能减退会导致耳蜗畸形，但在Thrb-/-小鼠中没有这种迹象。这些发现表明，Trβ控制听觉功能的成熟，但不控制耳蜗的形态发生。Thrb-/-小鼠为人类甲状腺激素抵抗（RTH）内分泌疾病提供了一个模型，该疾病通常与Trβ的显性突变有关。然而，RTH患者通常没有耳聋，这表明Trβ的显性和隐性突变对听觉系统有不同的影响。我们的结果确定Trβ是听觉发育的必需转录因子，并表明不同的Tr基因具有某些独特的功能。
