Overview

Mice homozygous for the beige spontaneous mutation (Lyst^bg) are characterized by a condition that closely resembles Chediak-Higashi disease in man and similar conditions in mink and cattle. Abnormal giant lysosomal granules occur in all tissues with granule-containing cells, including granulocytes, lymphocytes, cells of the liver, kidney, central nervous system, pancreas, and thyroid, and the ducts of most glands; in type II pneumocytes; in mast cells; and in retinal pigment epithelium. Granulocytes from beige homozygous mutant mice mice show defective chemotaxis and reduced bactericidal activity. Beige mice are more susceptible than controls to pneumonitis and to various viral, bacterial, and parasitic infections. Natural killer (NK) cells from beige mice exhibit decreased endogenous cytotoxic activity. Beige mice also have a defective cytotoxic T-cell and cytotoxic antibody response to allogeneic tumor cells. Syngeneic tumor cells grow better in beige mice than in l...

Genetic overview

Genetic Background	Generation
000664 C57BL/6J

Lyst^bg

Allele Type	Gene Symbol	Gene Name
Radiation induced	Lyst	lysosomal trafficking regulator

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Research Applications

Metabolism Research
Cardiovascular Research
Dermatology Research
Hematological Research
Immunology, Inflammation and Autoimmunity Research
Internal/Organ Research
Mouse/Human Gene Homologs
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Details

Detailed Description

Mice homozygous for the beige spontaneous mutation (Lyst^bg) are characterized by a condition that closely resembles Chediak-Higashi disease in man and similar conditions in mink and cattle. Abnormal giant lysosomal granules occur in all tissues with granule-containing cells, including granulocytes, lymphocytes, cells of the liver, kidney, central nervous system, pancreas, and thyroid, and the ducts of most glands; in type II pneumocytes; in mast cells; and in retinal pigment epithelium. Granulocytes from beige homozygous mutant mice mice show defective chemotaxis and reduced bactericidal activity. Beige mice are more susceptible than controls to pneumonitis and to various viral, bacterial, and parasitic infections. Natural killer (NK) cells from beige mice exhibit decreased endogenous cytotoxic activity. Beige mice also have a defective cytotoxic T-cell and cytotoxic antibody response to allogeneic tumor cells. Syngeneic tumor cells grow better in beige mice than in littermate controls, an effect thought to be due to the deficiency of NK cells. Beige mice have platelet storage pool deficiency, leading to a prolonged bleeding time. The immunodeficiency of beige mutant mice has been used, especially in combination with the scid mutation (Prkdc^scid), in tissue graft and disease studies.

Development

Both the satin (Foxq1^sa) and the original beige (Lyst^bg) recessive mutations arose at Oak Ridge National Laboratory in backcross test matings from T stock female x irradiated (101/Rl x C3H/Rl)F1 male. T stock was a multiple-recessive tester strain that contained several backgrounds including C57BL10/Rl. The two separate mutations, Foxq1^sa and Lyst^bg, were bred together and homozygous A^w/A^w Foxq1^sa Lyst^bg/Foxq1^sa Lyst^bg mice on a mixed background were received at The Jackson Laboratory in 1961. From the 5 mice imported one pair was bred brother x sister, both homozygous for Foxq1^sa, Lyst^bg and A^w, and this stock became strain SB/Le in 1971 at F42. The other mated pair was backcrossed to C57BL/6J keeping Foxq1^sa and Lyst^bg in coupling by the cross intercross system to N6. This stock was then sib mated to N6 F29 before 5 more backcrosses to C57BL/6J were made. At N11 Foxq1^sa was removed from the strain and sib matings of bg to N11F8 were made before 2 more crosses to C57BL/6J, made the stock N13 in 1982. The stock was cryopreserved in 1986 by mating homozygous Lyst^bg males at N13F16 to C57BL/6J females.

Genetics

Lyst^bg

Allele Symbol: Lyst^bg

Allele Name	beige
Allele Type	Radiation induced
Allele Synonym(s)	30B/22B; bg; CHS mice
Gene Symbol and Name	Lyst, lysosomal trafficking regulator
Gene Synonym(s)
Strain of Origin	C3H/Rl
Chromosome	13
Molecular Note	This allele is an insertion of a partial LINE 1 repetitive element into an intron of the gene. The insertion included only the most 3' 1097 bp of the element producing a frameshift mutation resulting in a truncated protein predicted to be missing the last 1442 amino acids.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Chediak-Higashi syndrome

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Lyst^bg related

Metabolism Research
Cardiovascular Research
- Atherosclerosis
Dermatology Research
- Color and White Spotting Defects
Hematological Research
- Immunological Defects
- Platelet Defects
  - platelet storage pool deficiency
Immunology, Inflammation and Autoimmunity Research
- CD Antigens, Antigen Receptors, and Histocompatibility Markers
- Immunodeficiency
- Intracellular Signaling Molecules
Internal/Organ Research
- Kidney Defects
  - lysosomal enzyme abnormalities
Mouse/Human Gene Homologs
- Chediak-Higashi syndrome
Research Tools
- Immunology, Inflammation and Autoimmunity Research
  - NK Cell Deficiency

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: A/? Lyst^bg/Lyst^bg Tyrp1^b/Tyrp1^b
Not Specified

integument phenotype

diluted coat color
- however, the relatively greater dilution effect noted on basal hair is not as pronounced in brown beige as in black beige mice
- on an agouti brown (A-bb) background, beige mice exhibit an overall cafe-au-lait coat color
- Background Sensitivity - the relatively greater dilution effect noted on basal hair is not as pronounced in brown beige as in black beige mice

pigmentation phenotype

decreased eye pigmentation
- Background Sensitivity - on an agouti brown (A-bb) background, newborn beige mice exhibit lighter eyes than on an agouti black (A-B-) background
- on an agouti brown (A-bb) background, newborn beige mice exhibit lighter eyes than on an agouti black (A-B-) background

diluted coat color
- however, the relatively greater dilution effect noted on basal hair is not as pronounced in brown beige as in black beige mice
- on an agouti brown (A-bb) background, beige mice exhibit an overall cafe-au-lait coat color
- Background Sensitivity - the relatively greater dilution effect noted on basal hair is not as pronounced in brown beige as in black beige mice

vision/eye phenotype

decreased eye pigmentation
- on an agouti brown (A-bb) background, newborn beige mice exhibit lighter eyes than on an agouti black (A-B-) background
- Background Sensitivity - on an agouti brown (A-bb) background, newborn beige mice exhibit lighter eyes than on an agouti black (A-B-) background

Genotype: a/a Lyst^bg/Lyst^bg
involves: C3H/Rl * C57BL/6J

pigmentation phenotype

abnormal choroid melanin granule morphology
- 80% of premelanosomes in the choroid and retina are fused to form giant granules

abnormal retinal melanin granule morphology
- 80% of premelanosomes in the retina and choroid are fused to form giant granules

vision/eye phenotype

abnormal choroid melanin granule morphology
- 80% of premelanosomes in the choroid and retina are fused to form giant granules

abnormal retinal melanin granule morphology
- 80% of premelanosomes in the retina and choroid are fused to form giant granules

The following phenotype relates to a compound genotype created using this strain

Genotype: Lyst^bg/Lyst^bg
B6.C3Rl-Lyst

behavior/neurological phenotype

abnormal vestibuloocular reflex
- mice exhibit an inverted optokinetic nystagmus in response to stimulation of only the temporal retina
- mice exhibit eye movements with a vertical component in response to horizontally moving, full-field stimuli

enhanced behavioral response to xenobiotic
- mutants exhibit increased sleeping time and prolonged bleeding times after treatment with pentobarbital, tribromoethanol, or the steroid anesthetic alphaxalone

growth/size/body region phenotype

increased kidney weight
- total weight of kidney is higher in mutants than in wild-type mice after androgen treatment

hearing/vestibular/ear phenotype

abnormal vestibuloocular reflex
- mice exhibit an inverted optokinetic nystagmus in response to stimulation of only the temporal retina
- mice exhibit eye movements with a vertical component in response to horizontally moving, full-field stimuli

hematopoietic system phenotype

abnormal eosinophil morphology
- all mice display giant granules in eosinophils from peripheral blood and bone marrow; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell
- giant granules are highly irregular and contain excessive numbers of clumped "crystalloids"

abnormal lymphocyte morphology
- all mice display giant granules in lymphocytes from peripheral blood and bone marrow, with an inner round density; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell

abnormal neutrophil morphology
- all mice display giant granules in neutrophils from peripheral blood and bone marrow; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell

decreased cytotoxic T cell cytolysis
- generation of cytotoxic T lymphocytes (CTLs) in response to alloimmune challenge in vivo or in vitro is impaired

impaired natural killer cell mediated cytotoxicity
- natural killer cell lysis activity toward tumor cells is impaired
- spleen cells fail to lyse a variety of natural killer cell sensitive targets, indicating impaired NK cytolysis

homeostasis/metabolism phenotype

abnormal urine enzyme level
- lower levels of urinary lysosomal enzymes

immune system phenotype

abnormal eosinophil morphology
- all mice display giant granules in eosinophils from peripheral blood and bone marrow; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell
- giant granules are highly irregular and contain excessive numbers of clumped "crystalloids"

abnormal lymphocyte morphology
- all mice display giant granules in lymphocytes from peripheral blood and bone marrow, with an inner round density; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell

abnormal neutrophil morphology
- all mice display giant granules in neutrophils from peripheral blood and bone marrow; not observed in control mice
- giant granules are found in a small percentage of cells, usually only 1 or 2 within a cell

alveolitis
- inflammation with infiltration of lymphocytes and macrophages in aged mice

decreased cytotoxic T cell cytolysis
- generation of cytotoxic T lymphocytes (CTLs) in response to alloimmune challenge in vivo or in vitro is impaired

impaired natural killer cell mediated cytotoxicity
- natural killer cell lysis activity toward tumor cells is impaired
- spleen cells fail to lyse a variety of natural killer cell sensitive targets, indicating impaired NK cytolysis

cellular phenotype

abnormal lysosome morphology
- abnormal lysosomes with high levels of acid phospahatse activity are detected in 15 of 23 tissues examined, including the liver, kidney, pancreas, cerebral cortex, cerebellum, spinal cord, bone marrow, peripheral blood, jejunum, as well as the thyroid, adrenal, gastic, lacrimal, submaxillary glands and sweat glands of the footpad
- anomalous lysosomes are enlarged, often more variable in size and shape and show a tendency to aggregate
- electron microscopy of liver and kidney revealed enlarged lysosomes containing numerous lipid-like inclusions
- mutants exhibit fusion of newly formed lysosomes in the promocytes and neutrophilic progranulocytes and in mature monocytes, neutrophils, and eosinophils, resulting in fewer but greatly enlarged lysosomes
- Normal - no alterations in lysosomal morphology are detected in striated muscle, duodenum, esophagus, epididymis, spleen or spleen node
- renal, gastic, lacrimal, submaxillary glands and sweat glands of the footpad
- the extent of anomaly varies from one tissue to another and within cells of a given tissue, ranging from extensive enlargement and aggregation of lysosomes in liver to a slight increase in size in sweat glands of the footpad
- the most striking alterations occur in liver parenchymal cells, kidney proximal tubule cells, Purkinje cells of cerebellum, and granulocytes of bone marrow and peripheral blood; no acid phosphatase activity was detected in melanocytes of the eye and skin where melanin granules have not been established as lysosomes
- where melanin granules have not been established as lysosomes

accumulation of giant lysosomes in kidney/renal tubule cells
- androgen-stimulated mutants exhibit an accumulation of giant glucuronidase-containing lysosomes in tubule cells near the croticomedullary boundary of the kidney

decreased lysosomal enzyme secretion
- androgen-treated mutants secrete only 1/3-1/4 as much of the above lysosomal enzymes as controls
- mutants secrete fewer units of glucuronidase, beta-galactosidase, and hexosaminidase than controls

lysosomal protein accumulation
- androgen-stimulated mutants exhibit an accumulation of the lysosomal enzymes, beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-D-glucosaminidase (hexosaminidase) in the kidneys, indicating defective process of extruding lysosomal enzymes through the plasma membrane of kidney tubule cells
- the plasma membrane of kidney tubule cells

integument phenotype

abnormal hair shaft melanin granule shape
- all mice display giant and irregular melanin granules in the medulla and cortex of hairs; not observed in control mice

neoplasm

altered tumor susceptibility
- a tumor line modified to be sensitive to NK cytotoxicity transplanted in mutants results in increased growth rate, faster induction time and an increased metastatic capability of the tumor

increased incidence of induced tumors
- mutants transplanted with virally and chemically induced leukemias develop palpable, progressively growing tumors faster and at a higher frequency than heterozygous controls

nervous system phenotype

abnormal hippocampal mossy fiber morphology
- infrapyramidal mossy fiber bundles originate from unrelated areas of the dentate gyrus instead of within the suprapyramidal mossy fiber layers as in controls
- infrapyramidal mossy fiber layers within area CA3 of the hippocampus appear to consist of discontinuous clumpings of diffusely scattered small bundles

abnormal hippocampus pyramidal cell layer
- the pyramidal cell layer is distorted within the CA3 area and appears as cell free-spaces within the cell layer or as few pyramidal cells ectopically scattered in the stratum orients

ectopic Bergmann glia cells
- arrangement of the Bergmann cells is more dispersed than in controls and a few ectopic Bergmann cells are located in the upper portion of the molecular layer

ectopic cerebellar granule cells
- clusters of ectopic granule cells in the molecular layer

ectopic hippocampus pyramidal cells
- a few pyramidal cells are ectopically scattered in the stratum orients

ectopic Purkinje cell
- ectopic Purkinje cells, mostly found in the lower half of the molecular layer as single cells

pigmentation phenotype

abnormal hair shaft melanin granule shape
- all mice display giant and irregular melanin granules in the medulla and cortex of hairs; not observed in control mice

abnormal melanocyte morphology
- all mice display giant, irregular melanin granules in retinal and choroidal melanocytes; not observed in control mice

abnormal melanosome morphology
- melanosomes are obviously enlarged and often aggregated
- unlike in control mice where mature eumelanin granules from skin, hair and eye are small, ovoid, deeply pigmented and 1-2 micra in diameter, giant melanin granules present in mutant mice are highly irregular and 2-10 micra in diameter

enlarged melanosome
- melanosomes are obviously enlarged

renal/urinary system phenotype

abnormal urine enzyme level
- lower levels of urinary lysosomal enzymes

accumulation of giant lysosomes in kidney/renal tubule cells
- androgen-stimulated mutants exhibit an accumulation of giant glucuronidase-containing lysosomes in tubule cells near the croticomedullary boundary of the kidney

increased kidney weight
- total weight of kidney is higher in mutants than in wild-type mice after androgen treatment

respiratory system phenotype

abnormal type II pneumocyte morphology
- marked swelling and degenerative changes of type II pneumocytes (referred to as "giant lamellar body degeneration" or GLBD) in aged mice
- progressive cytoplasmic foamy changes in type II pneumocytes from P0 to 24 months of age, increasing in terms of both the affected cell number and degree of severity as mice age

alveolitis
- inflammation with infiltration of lymphocytes and macrophages in aged mice

atelectasis
- patchy areas of alveolar collapse associated with marked GLBD, lymphocytic infiltration and slight fibrosis in aged mice

enlarged alveolar lamellar bodies
- most lamellar bodies are increased in size at P0
- numerous giant-sized lamellar bodies are often fused with each other in aged mice, often resulting in cellular distension and degeneration

overexpanded pulmonary alveoli
- enlarged air spaces in aged mice

pulmonary fibrosis
- no evidence of interstitial change in younger mice with only GLBD
- slight fibrosis in aged mice with prominent GLBD

Genotype: Lyst^bg/Lyst^bg
B6.C3Rl-Lyst/J

cellular phenotype

abnormal lysosome morphology
- light and electron microscopic cytochemistry of cultured fibroblasts shows large dense bodies have an origin through fusion of lysosomes

abnormal lysosome physiology
- significant increase in lysosomal enzyme activity of beta-galactosidase and beta-glucuronidase, and to a lesser extent N-acetyl-beta-hexoseaminidase, in kidney extracts

hematopoietic system phenotype

abnormal NK cell physiology
- lower natural killer cell activity

immune system phenotype

abnormal NK cell physiology
- lower natural killer cell activity

increased susceptibility to parasitic infection
- Normal - however, similar levels of anti-leishmanial antibody are produced by mutants as in controls and mutants exhibit a normal response to Leishmania tropica infection
- mutants fail to eliminate amastigotes of Leishmania donovani, the parasite causing leishmaniasis, from their spleens over 56 days

respiratory system phenotype

abnormal lung development

emphysema

impaired lung alveolus development
- alveolar maturation is impaired, resulting in abnormally large alveoli

References

Additional References

Schiller NK; Black AS; Bradshaw GP; Bonnet DJ; Curtiss LK. 2004. Participation of macrophages in atherosclerotic lesion morphology in LDLr-/- mice. J Lipid Res 45(8):1398-409PubMed: 15175354 MGI: J:91367

Additional - Lyst^bg related

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Citation
When using the B6.C3Rl-Lyst^bg/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #000204 in your Materials and Methods section.

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Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

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	Heterozygous for Lyst<bg>

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Genetic overview

Research Applications

Base Price

Detailed Description

Development

Lystbg

Allele Symbol: Lystbg

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Lystbg related

Mammalian Phenotype Terms by Genotype

Genotype: A/? Lystbg/Lystbg Tyrp1b/Tyrp1bNot Specified

integument phenotype

pigmentation phenotype

vision/eye phenotype

Genotype: a/a Lystbg/Lystbginvolves: C3H/Rl * C57BL/6J

pigmentation phenotype

vision/eye phenotype

Genotype: Lystbg/LystbgB6.C3Rl-Lyst

behavior/neurological phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

cellular phenotype

integument phenotype

neoplasm

nervous system phenotype

pigmentation phenotype

renal/urinary system phenotype

respiratory system phenotype

Genotype: Lystbg/LystbgB6.C3Rl-Lyst/J

cellular phenotype

hematopoietic system phenotype

immune system phenotype

respiratory system phenotype

References

Additional References

Additional - Lystbg related

Genotyping Protocols

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Lyst^bg

Allele Symbol: Lyst^bg

Genotype: Lyst^bg related

Genotype: A/? Lyst^bg/Lyst^bg Tyrp1^b/Tyrp1^b
Not Specified

Genotype: a/a Lyst^bg/Lyst^bg
involves: C3H/Rl * C57BL/6J

Genotype: Lyst^bg/Lyst^bg
B6.C3Rl-Lyst

Genotype: Lyst^bg/Lyst^bg
B6.C3Rl-Lyst/J

Additional - Lyst^bg related