A Model Of Mucopolysaccharidosis Type ?B (MPS ?B)Disease In Pigs

Pork is an important meat source for humans. In addition, pigs are more similar to humans than mice in genome, anatomy, physiology and disease traits, and raise less ethical concerns than non-human primates. The pig is thus an excellent biomedical model for humans. We have previously generated a batch of BMPR-IB transgenic pigs by somatic cell nuclear transfer. One copy of exogenous gene was inserted into exon 6 of the NAGLU gene on chromosome 12(SSC12) in one founder boar, leading to a frame-shift mutation in this gene. In human, loss-of-function mutations in NAGLU cause mucopolysaccharidosis type ?B(MPS ?B) disease. In this study, we produced F1 offsprings of the founder boar and F2 individuals derived from half-sib mating between F1 MPS ?B affected boars and sows. We conducted a series of analysis to characterize phenotypes of MPS ?B pigs, with the aim to provide an ideal large-animal model for human MPS ?B disease. Conventional PCR, multiplex PCR, relative quantification real-time PCR and absolute quantification real-time PCR were implemented to identify NAGLU-/- homozygous individuals in 45 F2 pigs and embryos at the age of 45 and 28 days. However, we did not find any homozygous individuals, indicating that NAGLU-/- homozygotes were embryonic lethal. Three F1 MPS ?B affected pigs and one unaffected pig were used for nuclear magnetic resonance(NMR), computed tomography(CT) scanning, and X ray analyses. Both NMR and CT scanning analyses showed that the affected pigs had a certain degree of brain atrophy. NMR also revealed abnormalities in brain internal capsule, frontal lobe and thalamus of affected pigs. Ventriculomegaly and cerebellar atrophy were also found in MPS ?B affected pigs by NMR. No obvious pathologic changes were found by X ray analysis. Obvious tissue degeneration and a lower level of NAGLU was found in brain and liver of three affected individuals(2.5 years) than in unaffected pig by immunohistochemical analysis. In conclusion, NAGLU+/- pigs have very similar pathological characteristics with human MPS ?B affected patients, supporting that these NAGLU+/- pigs is an ideal model for studies on the human MPS ? B disease.