High mobility group A2 (HMGA2) deficiency in pigs leads to dwarfism, abnormal fetal resource allocation, and cryptorchidism.

Abstract

Expression of <i>HMGA2</i> is strongly associated with body size and growth in mice and humans. In mice, inactivation of one or both alleles of <i>Hmga2</i> results in body-size reductions of 20% and 60%, respectively. In humans, microdeletions involving the <i>HMGA2</i> locus result in short stature, suggesting the function of the HMGA2 protein is conserved among mammals. To test this hypothesis, we generated HMGA2-deficient pigs via gene editing and somatic cell nuclear transfer (SCNT). Examination of growth parameters revealed that <i>HMGA2</i>^-/+ male and female pigs were on average 20% lighter and smaller than <i>HMGA2</i>^+/+ matched controls (<i>P</i> < 0.05). <i>HMGA2</i>^-/- boars showed significant size reduction ranging from 35 to 85% of controls depending on age (<i>P</i> < 0.05), and organ weights were also affected (<i>P</i> < 0.05). <i>HMGA</i>2^-/+ gilts and boars exhibited normal reproductive development and fertility, while <i>HMGA2</i>^<i>-</i>/- boars were sterile due to undescended testes (cryptorchidism). Crossbreeding <i>HMGA2</i>^-/+ boars and gilts produced litters lacking the <i>HMGA2</i>^-/- genotype. However, analysis of day (D) D40 and D78 pregnancies indicated that <i>HMGA2</i>^-/- fetuses were present at the expected Mendelian ratio, but placental abnormalities were seen in the D78 <i>HMGA2</i>^-/- concepti. Additionally, <i>HMGA2</i>^-/- embryos generated by gene editing and SCNT produced multiple pregnancies and viable offspring, indicating that lack of HMGA2 is not lethal per se. Overall, our results show that the effect of <i>HMGA2</i> with respect to growth regulation is highly conserved among mammals and opens up the possibility of regulating body and organ size in a variety of mammalian species including food and companion animals.