Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 Gene, Duox2
Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 Gene, Duox2
复制标题
DOI：
10.1210/me.2007-0085
复制
发表时间：
2007-07-01
影响因子：
--
通讯作者：
Donahue, Leah Rae
中科院分区：
文献类型：
--
作者：
Johnson, Kenneth R.;Marden, Coleen C.;Donahue, Leah Rae
双氧化酶产生甲状腺过氧化物酶所需的过氧化氢，以将碘掺入甲状腺球蛋白，这是甲状腺激素合成的重要步骤。人类双氧化酶2基因DUOX 2的突变已被证明是几例先天性甲状腺功能减退症的基础。我们在这里报告了第一个小鼠Duox 2突变，它为研究Duox 2在甲状腺和其他器官系统中的特定功能提供了一个新的遗传模型，假设它在这些系统中发挥作用。我们将新的自发小鼠突变定位于2号染色体，并将其鉴定为Duox 2外显子16中的T > G碱基对变化。该突变将氨基酸位置674（V674 G）的高度保守的缬氨酸变为甘氨酸，并被命名为“甲状腺激素生成障碍”（符号thyd），以表示甲状腺激素合成的缺陷。突变小鼠的甲状腺呈甲状腺肿状，几乎没有正常的滤泡，前垂体发育不良。纯合子的血清T-4水平约为对照组的十分之一，并伴有TSH增加100倍以上。成年突变小鼠的体重约为同窝对照小鼠的一半，血清IGF-I降低。突变小鼠的耳蜗表现出甲状腺功能减退症的特征性异常，包括内沟和Corti隧道的延迟形成和异常增厚的盖膜。成年突变小鼠的听力阈值平均比对照组高50-60分贝（dB）。
Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T > G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named "thyroid dyshormonogenesis" (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T-4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50-60 decibels (dB) above those of controls.