Date of Award
Master of Science
Genetics and Genomics
N. Matthew Ellinwood
The Mucopolysaccharidoses (MPS) are a class of lysosomal storage disorders, characterized by the primary lysosomal storage of either single or multiple species of glycosaminoglycan (GAG) which leads to cell, tissue, and organ dysfunction. This is manifested clinically by either bone/connective tissue disease, central nervous system (CNS) disease, or both, and often results in premature death. Mucopolysaccharidosis type III is a heterogeneous neuropathological disorder characterized by an accumulation of the heparan sulfate (HS). Of the four known types of MPS III in humans (A (OMIM: 252900), B (252920), C (252930), D (252940)), all have murine models except IIID. Additional to primary HS storage there is secondary lysosomal accumulation of multiple biological products including gangliosides. Mouse models are critical for advancing therapies for patients. Herein we describe the first mouse model of IIID.
The MPS IIID knockout lacks exons 2-13 of the 14 exons of N-Acetylglucosamine 6-Sulfatase (GNS) gene which encodes the enzyme (N-Acetylglucosamine 6-Sulfatase, EC 22.214.171.124) taking part in HS degradation pathway. Affected MPS IIID mice were compared to affected MPS IIIB and IIIA mice, as well as to wild type (WT) mice. Affected IIID animals had urine retention, hepatomegaly, and rough hair coat beginning at nine months, a phenotype similar to other forms of MPS III. Affected animals were further characterized by histology and biochemistry (at four, eight and twelve months), and behavior. At four months of age there was no detectable liver activity of GNS and an exponential increase of GAGs was seen. Mild vacuolation, particularly in CNS, was seen in hematoxylin and eosin (H&E) stained tissues of IIID affected mice. At twelve months H&E staining showed extensive vacuolation in hepatocytes, renal tubular cells, CNS, as well as cerebellar Purkinje cell loss. Luxol Fast Blue (LFB) staining of CNS tissue showed positive staining for glycosphingolipids. The preliminary behavioral assessment data showed that IIID mice perform better on rotorod at least until 12 months of age compared to IIIB mice.
Our findings of IIID mouse are consistent with the histological and biochemical findings in humans. Furthermore, it has a similar phenotype and pathology to other MPS III murine models.
Jamil, Maryam, "Characterization of a murine model of mucopolysaccharidosis type IIID: A knockout model" (2016). Graduate Theses and Dissertations. 15726.