Mouse Genome Informatics
hm
    Smpd1tm1Esc/Smpd1tm1Esc
involves: 129S1/Sv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• animals died at 6 to 8 months of age

behavior/neurological
• mild tremors at 8 weeks of age
• first noticeable at 8 weeks, severe by four months of age
• hunched appearance at death
• by 12-16 weeks, animals became lethargic, non-responsive to stimuli and had difficulty feeding

cellular
• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow
• similar to lymphoblasts from Niemann-Pick patients, lung tissue from homozygous mutant mice failed to respond to increasing doses of ionizing radiation with pulmonary ceramide generation and apoptosis; homozygotes were used within 3 weeks of weaning, that is, prior to the onset of disease manifestations
• compared to wild-type tissue, both thymic and splenic tissue from homozygous mutant mice displayed a significant reduction in radiation-induced apoptosis
• homozygotes were defective in LPS-induced ceramide generation, and exhibited decreased endothelial apoptosis and death

growth/size/body
• animals were half the weight of littermates and most major internal organs were smaller

homeostasis/metabolism
• lipid analysis revealed accumulation of sphingomyelin in both liver extracts (~15-fold) and brain extracts (~5-fold)
• lipid appeared to be accumulated in the livers of affected animals, but not in the brain
• characteristic, lipid laden foam cells ('NPD' cells) were found in most major organs, particularly in the bone marrow and spleen
• lipid accumulation was histologically evident in somatic cells of the gonads as well as in fully formed caudal spermatozoa
• at 6 months of age, mutant caudal spermatozoa exhibited elevated cholesterol accumulation in the plasma membrane, evidenced as an increase in filipin-sterol complexes over the acrosome
• increased total blood cholesterol levels; elevated nearly 80% in affected mice with most of the accumulating material associated with the HDL lipoprotein fraction

immune system
N
• homozygous mutant mice displayed a normal elevation in serum tumor necrosis factor (TNF) in response to LPS, indicating normal monocyte/macrophage activation (J:44401)
• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow
• macrophages and granulocytes from L. monocytogenes-infected homozygous mutant mice displayed normal production of both reactive nitrogen and oxygen intermediates
• resident peritoneal macrophages exhibited normal phagocytic uptake of FITC-labeled, viable L. monocytogenes; however, mutant macrophages were incapable of killing phagocytosed L. monocytogenes
• compared with syngeneic wild-type mice, homozygous mutant mice displayed a dramatically enhanced susceptibility to the intracellular bacterial pathogen L. monocytogenes (~100-fold)
• homozygous mutant mice also displayed an enhanced (but less dramatic) susceptibility to the facultative intracellular S. typhimurium, but not to the extracellular S. aureus

reproductive system
N
• affected males could breed until 20 weeks of age and females until 10 weeks of age; litter sizes were normal with slightly increased neonatal death among litters of affected females; increased death likely due to declining health of mothers (J:78875)
• wild-type mating pairs sired more litters, and of a larger size, than mating pairs of wild-type females and homozygous mutant males (J:78875)
• mating outcomes between two homozygous mutant mice produced the lowest average number and size of litter, suggesting that reproductive anomalies may also develop in the female gonads (J:78875)
• sperm formation and sperm numbers appeared normal; however, homozygous mutant males displayed a reproductive pathology characterized by lipid accumulation in the epididymal epithelia, abnormal osmolar regulation, and subsequent deficits in sperm maturation and function (J:78875)
• the vast majority of mutant sperm showed loss of plasma, acrosome, and mitochondria membrane integrity, as well as decreased mitochondrial membrane potential; the remaining membrane-intact sperm (13.4% in 6-month-old mice) failed to undergo proper capacitation (J:78875)
• in addition, mutant spermatozoa exhibited microcephaly, bending at the head-midpiece junction, coiling of the tail, decapitation, and small aggregates (J:78875)
• incubation of mutant sperm in a dilute detergent solution showed that dysmorphic spermatozoa reverted to a normal, straight position (J:78875)
• at 6 months of age, physically bent or hairpin sperm accounted for ~50% of mutant spermatozoa (J:78875)
• membrane-intact sperm (13.4% in 6-month-old mice) failed to undergo proper capacitation (J:78875)
• mutant sperm displayed severe tail retroflexion at the midpiece/principal piece junction associated with swollen cytoplasmic droplets, even when motile (J:78875)
• motile mutant sperm showed a reduction in swimming velocities (flagellar strength and forward progression) when compared with straight, wild-type sperm (J:78875)

nervous system
• brains were half the weight and volume of control animals
• electron microscopic analysis revealed numerous multilammellar, cytoplasmic inclusions in all tissues, particularly in brain
• atrophy of the midbrain
• atrophy of the cerebellum
• loss of Purkinje cells

hematopoietic system
• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow
• macrophages and granulocytes from L. monocytogenes-infected homozygous mutant mice displayed normal production of both reactive nitrogen and oxygen intermediates
• resident peritoneal macrophages exhibited normal phagocytic uptake of FITC-labeled, viable L. monocytogenes; however, mutant macrophages were incapable of killing phagocytosed L. monocytogenes

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type A 257200 J:26732 , J:35076 , J:44401 , J:70489 , J:78875 , J:81982
Niemann-Pick Disease, Type B 607616 J:26732 , J:35076 , J:44401 , J:70489 , J:78875 , J:81982