Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
PLoS One. 2012;7(1):e31035. doi: 10.1371/journal.pone.0031035. Epub 2012 Jan 27.
Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2(grt)) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129(+Ter)/SvJcl (129) mouse strain ameliorates Tpst2(grt)-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2(grt) mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.
酪氨酰蛋白硫酸转移酶 2（TPST2）是负责酪氨酸 O-硫酸化的酶之一，催化促甲状腺激素受体（TSHR）特定酪氨酸残基的硫酸化。由于这种修饰对于 TSH 信号的激活是必不可少的，因此 DW/J-grt 小鼠中的非功能性 TPST2 突变（Tpst2(grt)）导致先天性甲状腺功能减退症（CH），其特征为严重的甲状腺发育不全和 TSH 反应低下相关的侏儒症。先前的研究表明，129(+Ter)/SvJcl（129）小鼠品系的遗传背景改善了 Tpst2(grt)诱导的 CH。为了鉴定 129 小鼠中 CH 抗性的相关基因座，我们使用易感 DW/J 和抗性 129 小鼠的回交后代进行了数量性状基因座（QTL）分析。我们使用 5、8 和 10 周时体重的第一主成分作为 CH 的指标，并进行 QTL 分析，结果显示一个主要的 QTL 与染色体（Chr）2 的远端部分显著连锁；位于 D2Mit62 和 D2Mit304 之间，特别是靠近 D2Mit255。此外，还分别在 Chr4 和 Chr18 上检测到两个具有统计学意义的雄性特异性 QTL。所有来自 129 品系的 QTL 等位基因都增加了对生长迟缓的抗性。在雄性后代中，D2Mit255 处存在 129 等位基因与甲状腺发育恢复之间也存在正相关。这些结果表明 Chr2 上的主要 QTL 参与甲状腺发育。此外，由于携带 Tpst2(grt)突变和主要 QTL 中的 129 等位基因的 DW/J 同源基因系小鼠对侏儒症和甲状腺发育不全具有抗性，因此我们确认该区域存在抗性基因，并且该基因参与甲状腺发育。进一步的遗传分析应该导致 CH 耐受性基因的鉴定，并且从对甲状腺器官发生和功能的更好理解中，为甲状腺疾病的新治疗方法的后续开发奠定基础。
