Generation of a miniature pig disease model for human Laron syndrome.
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 (GHR(4bp/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. GHR(4bp/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.
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.|State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Dan
D
Cui
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Fang
F
Li
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Qiuyan
Q
Li
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Jia
J
Li
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Yaofeng
Y
Zhao
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Xiaoxiang
X
Hu
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Ran
R
Zhang
State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China.
Ning
N
Li
D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D046150:Laron Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature
D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone