Generation of a miniature pig disease model for human Laron syndrome.
Generation of a miniature pig disease model for human Laron syndrome.
复制标题
DOI：
10.1038/srep15603
复制
发表时间：
2015-10-29
影响因子：
4.6
通讯作者：
Li N
中科院分区：
文献类型：
--
作者：
Cui D;Li F;Li Q;Li J;Zhao Y;Hu X;Zhang R;Li N
Laron综合征是一种罕见的疾病，由生长激素受体（GHR）突变引起，以常染色体方式遗传。为了更好地了解发病机制和开发治疗方法，我们通过使用ZFN敲除GHR基因来建立这种疾病的小型猪模型。获得了三种类型的F0杂合子猪（GHR+/4 bp、GHR+/2bp、GHR+/3bp），其中未观察到明显的Laron综合征表型。在将杂合子猪培育成纯合子（GHR 4 bp/4 bp）之前，在体外评估具有4 bp插入物的猪GHR转录物，发现其定位于细胞质而不是细胞膜。此外，这种突变的转录本失去了大部分的信号转导能力，虽然它可以结合bGH。GHR 4 bp/4 bp猪表现出较小的体型和降低的体重。生化方面，这些猪表现出GH水平显著升高，IGF-I水平降低。这些结果类似于在Laron患者中观察到的表型，表明这些猪可以作为Laron综合征的理想模型，以弥合小鼠模型和人类之间的差距。
Laron syndrome is a rare disease caused by mutations of the growth hormone receptor (GHR), inheriting in an autosomal manner. To better understand the pathogenesis and to develop therapeutics, we generated a miniature pig model for this disease by employing ZFNs to knock out GHR gene. Three types of F0 heterozygous pigs (GHR+/4bp, GHR+/2bp, GHR+/3bp) were obtained and in which no significant phenotypes of Laron syndrome were observed. Prior to breed heterozygous pigs to homozygosity (GHR4bp/4bp), pig GHR transcript with the 4 bp insert was evaluated in vitro and was found to localize to the cytoplasm rather than the membrane. Moreover, this mutated transcript lost most of its signal transduction capability, although it could bind bGH. GHR4bp/4bp pigs showed a small body size and reduced body weight. Biochemically, these pigs exhibited significantly elevated levels of GH and decreased levels of IGF-I. These results resemble the phenotype observed in Laron patients, suggesting that these pigs could serve as an ideal model for Laron syndrome to bridge the gaps between mouse model and human.