Phenotypes Associated with This Genotype

Genotype
MGI:3028763

• Allelic Composition: Smpd1^tm1Esc/Smpd1^tm1Esc
• Genetic Background: involves: 129S1/Sv * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:26732 )

• animals died at 6 to 8 months of age

behavior/neurological

lethargy ( J:26732 )

• by 12-16 weeks, animals became lethargic, non-responsive to stimuli and had difficulty feeding

tremors ( J:26732 )

• mild tremors at 8 weeks of age

ataxia ( J:26732 )

• first noticeable at 8 weeks, severe by four months of age

hunched posture ( J:26732 )

• hunched appearance at death

cellular

increased macrophage derived foam cell number ( J:81982 )

• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow

abnormal male germ cell morphology ( 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

♂ • in addition, mutant spermatozoa exhibited microcephaly, bending at the head-midpiece junction, coiling of the tail, decapitation, and small aggregates

♂ • incubation of mutant sperm in a dilute detergent solution showed that dysmorphic spermatozoa reverted to a normal, straight position

teratozoospermia ( J:78875 )

♂ • at 6 months of age, physically bent or hairpin sperm accounted for ~50% of mutant spermatozoa

abnormal apoptosis ( J:35076 )

• 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

asthenozoospermia ( J:78875 )

♂ • mutant sperm displayed severe tail retroflexion at the midpiece/principal piece junction associated with swollen cytoplasmic droplets, even when motile

♂ • motile mutant sperm showed a reduction in swimming velocities (flagellar strength and forward progression) when compared with straight, wild-type sperm

growth/size/body

decreased body weight ( J:26732 )

• animals were half the weight of littermates and most major internal organs were smaller

homeostasis/metabolism

abnormal lipid homeostasis ( J:26732 )

• 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 circulating HDL cholesterol level ( J:26732 )

• 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

immune system phenotype ( J:44401 )

N • homozygous mutant mice displayed a normal elevation in serum tumor necrosis factor (TNF) in response to LPS, indicating normal monocyte/macrophage activation

increased macrophage derived foam cell number ( J:81982 )

• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow

abnormal granulocyte physiology ( J:81982 )

• 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

increased susceptibility to bacterial infection ( J:81982 )

• 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

reproductive system phenotype ( J:78875 )

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

N • wild-type mating pairs sired more litters, and of a larger size, than mating pairs of wild-type females and homozygous mutant males

N • 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

N • 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

abnormal male germ cell morphology ( 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

♂ • in addition, mutant spermatozoa exhibited microcephaly, bending at the head-midpiece junction, coiling of the tail, decapitation, and small aggregates

♂ • incubation of mutant sperm in a dilute detergent solution showed that dysmorphic spermatozoa reverted to a normal, straight position

teratozoospermia ( J:78875 )

♂ • at 6 months of age, physically bent or hairpin sperm accounted for ~50% of mutant spermatozoa

asthenozoospermia ( J:78875 )

♂ • mutant sperm displayed severe tail retroflexion at the midpiece/principal piece junction associated with swollen cytoplasmic droplets, even when motile

♂ • motile mutant sperm showed a reduction in swimming velocities (flagellar strength and forward progression) when compared with straight, wild-type sperm

impaired sperm capacitation ( J:78875 )

♂ • membrane-intact sperm (13.4% in 6-month-old mice) failed to undergo proper capacitation

nervous system

decreased brain size ( J:26732 )

• brains were half the weight and volume of control animals

• electron microscopic analysis revealed numerous multilammellar, cytoplasmic inclusions in all tissues, particularly in brain

midbrain atrophy ( J:26732 )

• atrophy of the midbrain

Purkinje cell degeneration ( J:26732 )

• loss of Purkinje cells

cerebellum atrophy ( J:26732 )

• atrophy of the cerebellum

hematopoietic system

increased macrophage derived foam cell number ( J:81982 )

• lipid laden foam cells are found in most major organs, particularly the spleen and bone marrow

abnormal granulocyte physiology ( J:81982 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:26732 , J:35076 , J:44401 , J:70489 , J:78875 , J:81982