Phenotypes for Smpd1 MGI:3028763 MGI Mouse

premature death ( J:26732 )

• animals died at 6 to 8 months of age

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

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

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 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

decreased body weight ( J:26732 )

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

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 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 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

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

• 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

• 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

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

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

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

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

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
Citing These Resources Funding Information Warranty Disclaimer, Privacy Notice, Licensing, & Copyright Send questions and comments to User Support.	last database update 12/10/2024 MGI 6.24