Mortensen Amanda H, Fang Qing, Fleming Michelle T, Jones Thomas J, Daly Alexandre Z, Johnson Kenneth R, Camper Sally A
Department of Human Genetics, University of Michigan, 5705 Medical Science II, 1241 Catherine St., Ann Arbor, MI, 48109-5618, USA.
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
Mamm Genome. 2019 Feb;30(1-2):5-22. doi: 10.1007/s00335-019-09792-6. Epub 2019 Feb 18.
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-Pou1f1 mice have profound deafness and both neurosensory and conductive hearing impairment, while DF/B-Prop1 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 Prop1 mice, and they produce less thyroglobulin during the neonatal period critical for establishing hearing. We previously crossed DW/J-Pou1f1 and Cast/Ei mice and mapped a major locus on Chromosome 2 that protects against hypothyroidism-induced hearing impairment in Pou1f1 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-Pou1f1 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.
甲状腺激素的母体和胎儿来源对许多器官系统的发育至关重要。甲状腺激素缺乏在小鼠和人类中会导致不同程度的智力残疾和听力障碍，但其差异的基础尚不清楚。为了探究这种差异，我们研究了两种甲状腺激素缺乏的小鼠突变体，它们在垂体特异性转录因子POU1F1和PROP1中发生了突变，导致无法产生促甲状腺激素。DW/J-Pou1f1小鼠患有严重耳聋，同时存在神经感觉性和传导性听力障碍，而DF/B-Prop1小鼠的听力阈值有适度升高，与发育迟缓一致，最终听力能力恢复正常。Pou1f1突变体的甲状腺比Prop1小鼠的甲状腺受到的影响更严重，并且在对建立听力至关重要的新生儿期产生的甲状腺球蛋白更少。我们之前将DW/J-Pou1f1和Cast/Ei小鼠进行杂交，并在2号染色体上定位了一个主要位点，该位点可保护Pou1f1小鼠免受甲状腺功能减退引起的听力障碍：dw听力修饰基因（Mdwh）。在这里，我们通过对196只动物进行876个信息性单核苷酸多态性（SNP）基因分型来细化Mdwh的位置，并且我们用DW/J-Pou1f1和129/P2杂交进行了新的定位，结果显示129/P2小鼠也有一个保护性的Mdwh位点。通过对DW/J和DF/B品系进行DNA测序，我们确定Mdwh内对甲状腺功能重要的基因在对甲状腺功能减退引起的听力障碍敏感或有抗性的品系之间氨基酸序列存在差异。这些结果表明，先天性甲状腺功能减退对听力发育的不同影响可归因于出生后甲状腺滤泡生成和功能的基因变异。
