Knockout technology has proven useful for delineating functional roles of specific genes. Here we describe and provide an explanation for striking pathology that occurs in a subset of genetically engineered mice expressing a rat CaVβ2a transgene under control of the cardiac α-myosin heavy chain promoter. Lesions were limited to mice homozygous for transgene and independent of native Cacnb2 genomic copy number. Gross findings included an atrophied pancreas, decreased adipose tissue, thickened, orange intestines, and enlarged liver, spleen and abdominal lymph nodes. Immune cell infiltration and cell engulfment by macrophages were associated with loss of pancreatic acinar cells. Foamy macrophages diffusely infiltrated the small intestine's lamina propria; while similar macrophage aggregates packed liver and splenic red pulp sinusoids. Periodic-acid-Schiff positive, diastase- resistant, iron-negative, Oil Red O positive, and autofluorescent cytoplasm was indicative of a lipid storage disorder. EM analysis revealed liver sinusoids distended by clusters of macrophages containing intracellular myelin "swirls" and hepatocytes with enlarged lysosomes. Additionally, build-up of cholesterol, cholesterol esters and triglycerides along with changes in liver metabolic enzyme levels were consistent with a lipid processing defect. Because of this complex pathology, we examined the transgene insertion site. Multiple transgene copies inserted into chromosome 19; at this same site an approximate 180,000 base pair deletion occurred, ablating cholesterol 25-hydroxylase and partially deleting lysosomal acid lipase and CD95. Loss of gene function can account for the altered lipid processing along with hypertrophy of the immune system, which define this phenotype and serendipitously provides a novel mouse model of lysosomal storage disorder.
- lysosomal storage disorders
- TNFR super family gene 6
- Copyright © 2016, American Journal of Physiology-Gastrointestinal and Liver Physiology