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首页> 外文期刊>Journal of the Association for Research in Otolaryngology: JARO >Hearing impairment in hypothyroid dwarf mice caused by mutations of the thyroid peroxidase gene
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Hearing impairment in hypothyroid dwarf mice caused by mutations of the thyroid peroxidase gene

机译：甲状腺过氧化物酶基因突变导致甲状腺功能减退小鼠的听力障碍

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摘要

Thyroid hormone (TH) is essential for proper cochlear development and function, and TH deficiencies cause variable hearing impairment in humans and mice. Thyroid peroxidase (TPO) catalyzes key reactions in TH synthesis, and TPO mutations have been found to underlie many cases of congenital hypothyroidism in human patients. In contrast, only a single mutation of the mouse TPO gene has been reported previously (TpoR479C) but was not evaluated for auditory function. Here, we describe and characterize two new mouse mutations of Tpo with an emphasis on their associated auditory deficits. Mice homozygous for these recessive mutations have dysplastic thyroid glands and lack detectable levels of TH. Because of the small size of mutant mice, the mutations were named teeny (symbol Tpotee) and teeny-2 Jackson (Tpotee-2J ). Tpotee is a single base-pair missense mutation that was induced by ENU, and Tpotee-2J is a 64 bp intragenic deletion that arose spontaneously. The Tpotee mutation changes the codon for a highly conserved tyrosine to asparagine (p.Y614N), and the Tpotee-2J mutation deletes a splice donor site, which results in exon skipping and aberrant transcripts. Mutant mice are profoundly hearing impaired with auditory brainstem response (ABR) thresholds about 60 dB above those of non-mutant controls. The maturation of cochlear structures is delayed in mutant mice and tectorial membranes are abnormally thick. To evaluate the effect of genetic background on auditory phenotype, we produced a C3.B6-Tpotee-2J congenic strain and found that ABR thresholds of mutant mice on the C3H/HeJ strain background are 10-12 dB lower than those of mutant mice on the C57BL/6 J background. The Tpo mutant strains described here provide new heritable mouse models of congenital hypothyroidism that will be valuable for future studies of thyroid hormones' role in auditory development and function.
机译：甲状腺激素（TH）对于正常的耳蜗发育和功能至关重要，而TH缺乏会导致人类和小鼠的听力障碍。甲状腺过氧化物酶（TPO）催化TH合成中的关键反应，并且已发现TPO突变是人类患者中许多先天性甲状腺功能减退症的基础。相反，以前仅报道了小鼠TPO基因的单个突变（TpoR479C），但未对其听觉功能进行评估。在这里，我们描述和表征两个新的Tpo小鼠突变，重点是它们相关的听觉缺陷。这些隐性突变的纯合子小鼠甲状腺发育异常，缺乏可检测的TH水平。由于突变小鼠的体型较小，这些突变被命名为teeny（符号Tpotee）和teeny-2 Jackson（Tpotee-2J）。 Tpotee是由ENU诱导的单个碱基对错义突变，而Tpotee-2J是自发产生的64 bp基因内缺失。 Tpotee突变将高度保守的酪氨酸的密码子更改为天冬酰胺（p.Y614N），而Tpotee-2J突变则删除了一个剪接供体位点，从而导致外显子跳跃和异常转录本。突变小鼠的听觉脑干反应（ABR）阈值比非突变对照组的阈值高约60 dB，严重损害了听力。在突变小鼠中，耳蜗结构的成熟被延迟，并且盖膜异常厚。为了评估遗传背景对听觉表型的影响，我们制备了一个C3.B6-Tpotee-2J同系菌株，发现在C3H / HeJ菌株背景下，突变小鼠的ABR阈值比在C3H / HeJ菌株背景下的突变小鼠低10-12 dB。 C57BL / 6 J背景。这里描述的Tpo突变株提供了先天性甲状腺功能减退的新的可遗传的小鼠模型，这对于将来研究甲状腺激素在听觉发育和功能中的作用将是有价值的。

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