Identifying quantitative trait loci affecting resistance to congenital hypothyroidism in 129/SvJcl strain mice.
Identifying quantitative trait loci affecting resistance to congenital hypothyroidism in 129/SvJcl strain mice.
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DOI：
10.1371/journal.pone.0031035
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Agui T
中科院分区：
文献类型：
--
作者：
Hosoda Y;Sasaki N;Kameda Y;Torigoe D;Agui T
酪蛋白磺基转移酶2（TPST 2）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信号传导的激活是必不可少的，DW/J-grt小鼠中的非功能性TPST 2突变（Tpst 2grt）导致先天性甲状腺功能减退症（CH），其特征在于与TSH低反应性相关的严重甲状腺发育不全和侏儒症。先前的研究表明，129+Ter/SvJcl（129）小鼠品系的遗传背景改善Tpst 2grt诱导的CH。为了确定129小鼠中负责CH抗性的基因座，我们使用易感DW/J和抗性129小鼠的回交后代进行数量性状基因座（QTL）分析。我们使用第一个主成分计算体重在5，8和10周作为CH的指标，QTL分析定位一个主QTL显示了一个高度显着的连锁染色体（Chr）2的远端部分之间的D2 Mit 62和D2 Mit 304，特别是接近D2 Mit 255。此外，在第4和第18个染色体上还检测到两个雄性特异的QTL，显示出统计学上的连锁性。来自129品系的所有QTL等位基因都增加了对生长迟缓的抗性。在雄性后代中，甲状腺发育不全的恢复与D2 Mit 255的129等位基因的存在也呈正相关。这些结果表明，Chr 2上的主效QTL与甲状腺发育有关.此外，由于DW/J同源系小鼠携带Tpst 2grt突变和129个等位基因的主要QTL显示抗性侏儒症和甲状腺发育不全，我们证实了抗性基因的存在，在这个地区，它是参与甲状腺发育。进一步的遗传学分析将导致CH耐受性基因的鉴定，并从更好地了解甲状腺器官发生和功能，随后开发甲状腺疾病的新治疗方法。
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 (Tpst2grt) 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 Tpst2grt-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 Tpst2grt 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.
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影响因子：
1.2
作者：
Hosoda, Yayoi;Sasaki, Nobuya;Agui, Takashi
通讯作者：
Agui, Takashi
影响因子：
4.8
作者：
Grasberger, Helmut;Refetoff, Samuel
通讯作者：
Refetoff, Samuel
影响因子：
4.8
作者：
Amendola, Elena;Sanges, Remo;Di Lauro, Roberto
通讯作者：
Di Lauro, Roberto
影响因子：
--
作者：
Johnson, Kenneth R.;Marden, Coleen C.;Donahue, Leah Rae
通讯作者：
Donahue, Leah Rae
影响因子：
2.5
作者：
Manly, KF;Cudmore, RH;Meer, JM
通讯作者：
Meer, JM