A model of mucopolysaccharidosis type IIIB in pigs.

Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder caused by loss-of-function mutations in the NAGLU gene. Pigs are an ideal large animal model for human diseases; however, a porcine model of MPS IIIB has not been reported. We have previously generated a heterozygous NAGLU-deficient (NAGLU +/-) Large White boar via a transgenic approach. Here we characterized phenotypes of the F1 offspring of this founder to establish a pig model for MPS IIIB. qRT-PCR revealed that the NAGLU expression level was significantly decreased in a variety of tissues in NAGLU +/- pigs. ELISA assays showed obvious deficiency of NAGLU and higher (P<0.05) glycosaminoglycan levels in multiple tissues from NAGLU +/- pigs. NAGLU +/- pigs grew at a significantly (P<0.05) slower rate than control animals (NAGLU +/+). Death, mostly sudden death, occurred at all ages in NAGLU +/- pigs, most of which died within two years. Necropsy findings included pleural adhesions, lung shrinkage and abnormalities in the pericardium and mild hepatomegaly in NAGLU +/- pigs. Notable pathological changes were observed in the sections of brain, liver, spleen and kidney from NAGLU +/- pigs. Brain atrophy, ventriculomegaly, cerebellar atrophy and abnormalities in the intracerebral capsule, parietal lobes and the thalamus were also evident in NAGLU +/- pigs. Together, NAGLU +/- pigs show typical symptoms of human MPS IIIB patients and thus represent a novel large animal model for the disease.This article has an associated First Person interview with the first author of the paper.