| Year | 2019 | Journal | J Am Assoc Lab Anim Sci |
| Volume | 58 | Issue | 5 |
| Pages | 607-726 | PubMed ID | 31547903 |
| Mgi Jnum | J:301674 | Mgi Id | MGI:6507027 |
| Citation | Ochoa-Dragos Z, et al. (2019) Lysosomal Storage Disease Caused by a Spontaneous Hexb Gene Mutation in immunodeficient NOD.Cg-Prkdc |
| abstractText | Spontaneous mutations provide a source of novel disease models in colonies of mice and other laboratory species. We recently identified a heritable tremoring phenotype in a colony of immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Pedigree analysis showed that the condition was inherited as a recessive trait with a median head tremor onset of 4.6 mo in both males (n=4) and females (n=6). Histologic changes were consistent with a neurovisceral storage disease with cytoplasmic vacuolation in neurons from the central and peripheral nervous system. Cytoplasmic vacuolation was also seen in a wider range of epithelia (gall bladder, bile duct, urinary bladder, renal tubular, bronchiolar, and mammary gland epithelium) and in phagocytes within the spleen and uterine endometrium. Cryoelectron microscopy revealed additional ultrastructural changes that included membranous cytoplasmic bodies, zebra bodies, and myelin edema. Whole genome sequencing identified a 6 nucleotide deletion in the hexosaminidase B (Hexb) gene in 2 affected mice that was not present in an unaffected NSG mouse or the inbred NOD/ShiLtJ reference genome. Hexb encodes a protein, beta-hexosaminidase B, that catalyzes lysosomal degradation of sphingolipids and other macromolecules; recessive mutations of the human homolog HEXB cause Sandhoff disease, a lysosomal storage disease. The putative mutation, Hexblysd, was predicted to be in-frame and result in deletion of 2 amino acids from the protein. Genetic evidence for the causative role of Hexblysd was found when this mutation failed to complement a null allele (Hexbtm1Rlp): all compound heterozygous (Hexblysd/tm1Rlp) and homozygous mutant mice (Hexblysd/lysd and Hexbtm1Rlp/tm1Rlp) developed tremors, while no tremors were observed in either heterozygous genotype during an 8+-mo period. Median time to initial symptoms was 3.8 mo in Hexblysd/lysd, 4.0 mo in Hexbtm1Rlp/tm1Rlp, and 4.3 months in Hexblysd/tm1Rlp. Hexblysd was backcrossed 5 generations to C57BL/6J to create a congenic strain with similar disease incidence (median of 3.8 mo). Our efforts describe a novel mutant mouse model of Sandhoff disease and highlight the value of whole-genome sequencing in identifying spontaneous mutations. |
