Maternal and fetal sources of thyroid hormone are important for the development of many organ systems. Thyroid hormone deficiency causes variable intellectual disability and hearing impairment in mouse and man, but the basis for this variation is not clear. To explore this variation, we studied two thyroid hormone-deficient mouse mutants with mutations in pituitary-specific transcription factors, POU1F1 and PROP1, that render them unable to produce thyroid stimulating hormone. DW/J-Pou1f1dw/dw mice have profound deafness and both neurosensory and conductive hearing impairment, while DF/B-Prop1df/df mice have modest elevations in hearing thresholds consistent with developmental delay, eventually achieving normal hearing ability. The thyroid glands of Pou1f1 mutants are more severely affected than those of Prop1df/df mice, and they produce less thyroglobulin during the neonatal period critical for establishing hearing. We previously crossed DW/J-Pou1f1dw/+ and Cast/Ei mice and mapped a major locus on Chromosome 2 that protects against hypothyroidism-induced hearing impairment in Pou1f1dw/dw mice: modifier of dw hearing (Mdwh). Here we refine the location of Mdwh by genotyping 196 animals with 876 informative SNPs, and we conduct novel mapping with a DW/J-Pou1f1dw/+ and 129/P2 cross that reveals 129/P2 mice also have a protective Mdwh locus. Using DNA sequencing of DW/J and DF/B strains, we determined that the genes important for thyroid gland function within Mdwh vary in amino acid sequence between strains that are susceptible or resistant to hypothyroidism-induced hearing impairment. These results suggest that the variable effects of congenital hypothyroidism on the development of hearing ability are attributable to genetic variation in postnatal thyroid gland folliculogenesis and function.

中文翻译：

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甲状腺滤泡发生的遗传变异会影响对甲状腺功能减退症诱发的听力障碍的敏感性。

甲状腺激素的母体和胎儿来源对许多器官系统的发育都很重要。甲状腺激素缺乏会引起小鼠和人的智力障碍和听力障碍，但这种变化的基础尚不清楚。为了探索这种变化，我们研究了两个垂体特异性转录因子POU1F1和PROP1突变的甲状腺激素缺陷型小鼠突变体，这些突变体使它们无法产生甲状腺刺激激素。DW / J-Pou1f1dw / dw小鼠患有严重的耳聋，并且神经感觉和传导性听力均受损，而DF / B-Prop1df / df小鼠的听力阈值适度升高，与发育延迟一致，最终达到正常的听觉能力。与Prop1df / df小鼠相比，Pou1f1突变体的甲状腺受影响更严重，并且它们在新生儿时期对建立听力至关重要的甲状腺球蛋白减少。我们以前越过DW / J-Pou1f1dw / +和Cast / Ei小鼠，并在2号染色体上绘制了一个主要基因座，该基因座可防止Pou1f1dw / dw小鼠甲状腺机能减退引起的听力障碍：dw听力的调节剂（Mdwh）。在这里，我们通过对876只信息丰富的SNP进行196只动物的基因分型来完善Mdwh的位置，并用DW / J-Pou1f1dw / +和129 / P2杂交进行了新颖的定位，揭示了129 / P2小鼠也具有Mdwh保护基因座。使用DW / J和DF / B菌株的DNA测序，我们确定了Mdwh中对甲状腺功能重要的基因在易感甲状腺功能减退或诱发甲状腺功能减退引起的听力障碍的菌株之间的氨基酸序列不同。