Mutants

Beige (bg)

Gene: This mutation, on chromosome 13, arose independently in several institutions in the 1950s and 1960s. 

Pathophysiology: Homozygotes are light in color. Phenotypes are similar to humans with Chédiak-Higashi syndrome, mink with the Aleutian trait, and Hereford cattle that are partially albino. They have abnormally large lysosomal granules in many cells (which make them good markers in chimeras). Defects occur in cytotoxic T cells and macrophages. Neutrophils are poor at chemotaxis and bactericidal functions. The natural killer (NK) cells are unable to kill tumor cells. Although they have reduced lytic activity, the NK cells are present in normal numbers and produce cytokines.{4578} Homozygotes are more susceptible to infection with pyogenic bacteria despite normal levels of immunoglobulins. Experimentally they have played a role in understanding hematopoietic differentiation.

Husbandry: Pathogen-free environment; barrier isolation not required. They are susceptible to many infectious agents, but not those that are indigenous to normal mice. Both sexes will breed.{4162}

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Diabetes (db)

Gene: Chromosome 4, discovered in C57BLKS/J and transferred to other inbred strains. Many alleles are present at the db locus.

Defect is in the leptin receptor. There is only one gene for leptin; the protein is cleaved by alternative splicing to result in at least 5 forms. The db/db mouse does not produce the long form (OB-RL). Lack of leptin receptors leads to high leptin levels but the effects (decreased appetite and increased energy) do not occur. {4172}

Pathophysiology: Marked obesity, hyperphagia, hyperinsulinemia and severe insulin resistance; however only some strains develop non-insulin-dependent diabetes mellitus (type II) with hyperglycemia, reduced insulin and islet atrophy. In the original strain, both sexes developed early-onset NIDDM; however, C57BL/6J-db/db mice compensate with hyperplasia of beta cells and sustained hyperinsulinemia. There are features of autoimmunity involved with the diabetes development, and C57BLKS/J-db/db mice have been useful to analyze the effects of NIDDM on the immune system.

Husbandry: No special needs. Not all strains will breed, and females are hypogonadal; therefore, heterozygotes must be used.{4162}

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Hairless (hr) and Rhino (hr^rh)

Gene: Recessive mutation hr, located on chromosome 14, was discovered in a wild mouse caught in London in 1924. The defect is a provirus integration at the locus. The HRS/J strain is a cross between an outbred stock with the mutation and BALB/cGn. The rhino mouse is maintained as an inbred strain with forced heterozygosity, RHJ/LeJ; this is because, as stated below, the mice aren't good parents, although they are fertile.

Pathophysiology: Hairless mice are euthymic, and develop normal pelage until about 10 days of age, at which time the hair falls out. They often develop cysts in the hair follicles and sebaceous glands. Homozygotes have a very high (45%) incidence of thymic lymphoma by 6 months of age. Due to problems with macrophage killing ability, the mice are highly susceptible to infection with Listeria monocytogenes. Rhino mice are also hairless, but their skin thickens and develops ridges. They also have decreased response to thymic-dependent antigens, possibly due to lower T helper cell function. Rhino mice are used to study comedolytic and anti-keratinizing agents. Although hair grows initially, at the end of the first hair cycle the follicular papillae fail to do what they're supposed to and become isolated inside the dermis. The hair follicle remnants get filled with sloughed debris, which expands the surface of the skin causing the ridges.

Husbandry: The mice can be housed conventionally, with their major problem being skin abscesses. Homozygote females don't nurse their young very well, so the best breeding scheme is heterozygous female x homozygous male.{4162}

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Motheaten (me), Viable motheaten (me^v)

Gene: Spontaneous mutant (1965) on chromosome 6. Both mutations arose in C57BL/6J strains. The viable motheaten mutant allele has increased longevity (~8 weeks in C57BL/6-me^v/me^v), whereas the original mice live only about 3 weeks. Mice have patchy alopecia, are small and die from pneumonia. The mutation has been backcrossed onto several strains (C3H/HeN, C3HB/FeJLe, C57BL/6N, NFS/N, NZB/N and P/N. Viable mutants are available on AKR/J, C3H/HeJ, DBA/2J, MRL/Mp and SJL/J strains.

Pathophysiology: C57BL/6J-me/me have the shortest lifespan of any mouse with a single mutation of the immune system, only about 3 weeks. On other strains, homozygotes live to 6-8 weeks. At 3 weeks, the thymus involutes, there is splenomegaly, there are no follicles in the lymph nodes, and there are other defects. Both cellular and humoral immunity are affected.

Husbandry: Lifespan is not increased by housing under germ-free conditions, so normal husbandry is provided. Heterozygotes can be bred, or homozygous female ovaries transplanted to histocompatible hosts and mated to normal males.{4162}

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Nude (Foxn1^nu) and Streaker (Foxn1^nu-str)

Gene: Autosomal recessive mutation on chromosome 11. Nude arose in a closed colony in Scotland, and streaker arose in AKR/J at Jackson Lab. The nude mutation was first described by Flanagan in 1966{4578}. Both have been transferred to many inbred strains.{4578} Human disease is DiGeorge's syndrome, according to the Army quoting from fascicle 144.

Pathophysiology: Two major defects: failure of hair growth (the vibrissae are crinkled or absent) and failure of the thymus to develop from the third pharyngeal pouch. The T-cell precursors are normal, and the mouse can be restored to normal T cell function with transplanted mature T cells, thymocytes or thymic epithelium. Subsets of T cells still develop as expected in other sites, i.e. the GIT and liver.{4578} Levels of immunoglobulin are reduced for unknown reasons. The AKR/J-Foxn1^nu-str/+ strain does not have the thymic lymphoma characteristic of the parent strain, making them interesting animals for study of the interactions among thymus function, MuLV infection and lymphomagenesis. The major use of nude mice is for oncogenesis. Graft failures are usually due to NK cells; "the nude mouse is not an immunologically inert mouse."{4578}

Husbandry: Should be maintained in germfree, defined-flora or pathogen-free environments for normal lifespan.{4162}

Nude (nu) + Dominant hemimelia (Dh) double mutants

Commonly known as lasat mice ("lacks a spleen and thymus") are both athymic and asplenic.

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Obese (ob)

Gene: Spontaneous autosomal recessive mutant on chromosome 6 discovered in 1949 at Jackson Lab; maintained on C57BL/6J and C57BL/KsJ backgrounds.

Pathophysiology: Marked obesity, hyperglycemia, hyperinsulinemia, insulin resistance. First mouse studied for obesity, is also diabetic. There is a marked background strain difference: C57BL/6J-ob/ob mice compensate by pancreatic beta cell hyperplasia and have mild transient hyperglycemia in males, whereas C57BL/KsJ-ob/ob mice have beta cell necrosis, normal serum insulin with severe insulin resistance, and severe hyperglycemia with death at 6-8 months.{4162}

When joined by parabiosis to a normal mouse, both obesity and diabetes are cured. The ob gene product is leptin, discovered by Jeff Friedman in 1994; when given to an ob/ob mouse it cures the obesity. Defect is a missense mutation such that functional leptin is not produced in white adipose tissue. The mice are also hypothermic, 1-2 degrees cooler than normal; has to do with brown adipose tissue, of which rodents have a lot.{4172} Homozygous ob/ob mice sleep for shorter times under pentobarbital than do heterozygotes.{4154}

Husbandry: No special procedures, although dietary restriction prolongs life. Obese mice are infertile, so use heterozygotes for breeding which are generally produced by ovarian transplantation.{4162}

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Rag1 and Rag2 null

These mice have similar cell deficiencies as scid mice (see below), and were created by deleting one of the two recombinase activation genes Rag1 or Rag2. These genes act earlier in development than the scid gene. They have been used, for example, in studies of xenografts. Porcine skin can be grafted onto a Rag1 null mouse, and the mouse reconstituted with human peripheral blood leukocytes to study destruction of the graft.{4578}

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Severe Combined Immunodeficiency (scid)

Gene: Spontaneous autosomal recessive on chromosome 16 that arose in C.B-Igh-1^b (aka C.B-17) congenic strain. In this strain, the inbred BALB/c carries the immunoglobulin heavy chain allele Igh-1^b of the C57BL/Ka strain. Phenotypically they look normal.

Pathophysiology: No immunoglobulin and no thymus; small lymph nodes, spleen and thymus. Mice can't reject allogeneic grafts or produce antibodies. They are better recipients than nude mice for transplantation studies, supporting a broader range of xenogenic tissues{4578}. However, 2-20% of adults are "leaky" in that they develop low numbers of B and T cells. Interestingly, about 15% of scid mice develop thymic lymphomas. They are very sensitive to being irradiated{4578}. Cells of myeloid lineage (granulocytes, erythrocytes and macrophages) are normal, as are NK cells. Homozygotes can be cured of lymphocyte deficiency by engraftment with bone marrow or fetal liver cells. Because scid mice are susceptible to pathogens such as Pneumocystis murina, they are good models for studying the relationship between immunity and disease.

Husbandry: Maintain in barrier conditions. Homozygous animals can be bred, but litter size is small (4-6) and mothering of such small litters is sometimes a problem. {4162}

Prkdc^scid

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Dominant Spotting (W), Viable Dominant Spotting (W^v)

Gene: Many alleles on chromosome 5 which are semi-dominant. The mutation was preserved by mouse fanciers from the early 20th century. Maintained on several backgrounds; the compound mutant W/W^v is maintained on WB/ReJ x C57BL/6J F₁ (WBB6F₁) background.

Pathophysiology: Homozygotes are white with black eyes, are sterile and have macrocytic anemia. Heterozygotes have white spots and slightly dilute coat color, have normal erythrocyte numbers or slight macrocytic anemia, and they are fully viable and fertile. There appear to be intrinsic defects in erythrocyte and melanocyte progenitor cells.

Husbandry: No special procedures needed; W homozygotes will only live for a week or so after birth. Heterozygotes are bred to produce affected animals.

WB/Rej-W/+ x C57BL/6J-W^v/+ produces W/W^v progeny, which are white. Heterozygotes have a white spot on the abdomen.{4162}

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Wasted (wst)

Gene: Spontaneous autosomal recessive lethal mutation arising in the HRS/J strain at Jackson in 1972. Maps to chromosome 2. Was crossed to segregating F1 hybrid background to increase viability (C3HeB/FeLe-a/a x C57BL/6J F₁) and is by now probably also available on C57BL/6J.

Pathophysiology: Neurologic signs (tremors, ataxia, paralysis) and death at <30 days of age. Similar to humans with ataxia telangiectasia, but there is controversy about how good a model they are.

Husbandry: no special procedures. Mate heterozygotes to produce them.

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X-linked Immune Deficiency (xid)

Gene: Sex-linked recessive originating in CBA/HN and now propagated on several backgrounds.

Pathophysiology: Homozygous females and hemizygous males have defective B cells. T cells are normal. Strain differences are significant in degree of impairment.

Husbandry: No special procedures. Maintain by brother x sister mating.{4162}

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Yellow (A^y)

These mice have yellow haircoats. They are obese and have increased tumor incidence. This mutation in the agouti gene is homozygous lethal.{4535}

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Y-linked Autoimmune Accelerator (Yaa)

Gene: Y-consomic stocks were developed by backcross of the Y chromosome of BXSB and C57BL/6J and vice versa. Inheritance is holandric, that is, transferred on the Y chromosome.

Pathophysiology: BXSB-Yaa males are smaller than females and develop lymphadenopathy by 3-4 months of age. The spleen is very large. Days before death (4-6 months), they develop generalized edema. During life they remain healthy, but they have immune complex disease and are anemic. C3H/HeJ-Yaa and SJL/J-Yaa males do not have autoimmunity.

Husbandry: No special procedures required. BXSB/Mp females breed well, but the males only live to produce 2-3 litters.{4162}

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Combined Mutants

tge26

This mouse carries multiple copies of a human gene. It has both an NK cell deficiency and a T cell deficit.{4578}

Ikaros null

All lymphocytes have been deleted. {4578}

gc

NK and T cell deficient mouse with the common cytokine receptor chain gamma deleted.

Rag2 null/gc null

These mice have no lymphocytes. They are commercially available and are being used as graft recipients for murine and xenogenic tissues. This mouse is expected to become the most important new strain since scid. It is a good breeder, free of lymphomas, and is more immune deficient than either scid or nude.{4578}

SCID-bo

These are C.B-17 scid-bg mice that have been transplanted with fetal bovine liver, lymph node and thymus. They can produce primary and secondary bovine humoral response to T-cell-dependent antigens and long-term self-sustaining bovine hematopoiesis. Unfortunately, this xenotransplantation can come with a price and we must be extremely vigilant with such animals!{4583}

NOD SCID

In the US the Harlan nomenclature is NOD.CB17-Prkdc^scid/NCrHsd; in the EU it's NOD.CB17/JHliHsd-Prkdc^scid . The Charles river strain is NOD.CB17-Prkdc^scid/NcrCrl; the Jax strain is NOD.CB17-Prkdc^scid/J.

NOD SCIDs are albino mice with severe combined immunodeficiency, and poor NK cell function. The mutation was transferred from the C.B-17 background onto the NOD background; the mice are not diabetic because of the T cell malfunction. The mice are significantly less "leaky" than SCID mice. They were developed in 1999 by Jax to serve as models for engraftment of malignant human cells.

Inbred Mouse Strains

BXSB/Mp females

Genetics: Recombinant inbred strain, agouti color, derived from a cross between C57BL/6J female and SB/Le male. The SB/Le strain has both bg and satin (sa), but these alleles were removed during the inbreeding from BXSB/Mp mice. SB/Le females develop autoimmune disease.

Pathophysiology: Females develop lymphoid hyperplasia, splenomegaly and Coombs' positive hemolytic anemia at a much older age than their male siblings. At necropsy they have chronic immune complex glomerulonephritis and vascular disease.

Husbandry: No special procedures.

MutaMouse

This is a transgenic mouse used for short-term detection of mutagens. It is similar to the Big Blue mouse and rat.{4535}

Non-Obese Diabetic (NOD)

Genetics: albino mice derived from ICR/Jcl by selection for insulin-dependent diabetes. The basis is polygenic, with at least 2 alleles (Idd-1 and Idd-2) on different chromosomes.

Pathophysiology: Similar to human type I diabetes (early onset, ketonuria, hyperglycemia, glucosuria, hypercholesterolemia, PU/PD/PP). T cells infiltrate islets and cause insulitis. Females develop diabetes earlier and more often than males; oddly, if males are housed under germ-free conditions, incidence rises dramatically (to 70%), indicating that immune stimulation causes them to protect themselves against the autoimmune cells. NOD-nu/nu mice do not develop diabetes unless reconstituted with T cells.

Husbandry: Without insulin, mice survive only 1-2 months after diagnosis. Less-purified diets containing grains cause them to develop diabetes later. NOD mice are maintained by brother x sister mating and breed well. A single injection of Freund's complete adjuvant can prevent breeders from developing diabetes.{4162}

Non-Obese Normal (NON) (which are neither!)

Genetics: Originally separated from the NOD line at the 6th generation, these were supposed to be the spontaneously-diabetic line while the parents were supposed to be the controls. However, spontaneous diabetes developed in the NOD line, and NON mice are neither normal nor non-obese!

Pathophysiology: Males develop high glucose after weaning and become obese by 20 weeks. Islets remain normal morphologically, but severe kidney lesions develop.

Husbandry: no special procedures. They reproduce normally, with small litters.

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New Zealand Black (NZB)

Genetics: Produced by inbreeding by selecting for coat color, and used to study autoimmune disease, with polygenic inheritance. 

Pathophysiology: Coombs'-positive hemolytic anemia reaching 100% incidence by 12-15 months. Used for research in iron deficiency and transport defects, as are NZW which have similar defects{4181}. There may be both T and B cell defects. B cells are hyperactive.

Husbandry: Maintain in pathogen-free environment, as viral infections alter the course of autoimmune disease. The strain breeds normally.{4162}

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NZB x NZW F₁ Hybrids

Genetics: These hybrids (aka BWF₁) develop a syndrome similar to systemic lupus erythematosus (SLE). Inheritance is polygenic. 

Pathophysiology: Antibodies to nucleic acids, progressive immune complex glomerulonephritis, and the disease is worse in females. Renal deposits of IgG, antigen and complement on the glomerular capillary basement membrane ultimately cause renal insufficiency and death by 12-14 months in females and 19 months in males. Deposition of immune complexes in the heart leads to thrombotic changes and myocardial infarction. 

Husbandry: Maintain in pathogen-free environment. Both parental strains breed normally.

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Palmerston North (PN)

Genetics: Originated in albino mice from a New Zealand pet store in 1948. They were bred at Palmerston North Hospital and eventually were imported into the US in 1974. 

Pathophysiology: Used as a model for SLE, and die from renal disease and vasculitis. A unique feature is the development of ANA or anti-DNA antibodies in newborn PN/Sw mice. 

Husbandry: no special procedures, and they breed normally.{4162}

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Senescence-Accelerated Mouse (SAM)

Genetics: Established by inbreeding from AKR/J mice selected for short lifespan.

Pathophysiology: At around 6 months, they become lethargic and develop alopecia, coarse skin, lordokyphosis, cataracts and osteoporosis. SAM-P/1 strain develops age-associated amyloidosis. T and NK activity is depressed.

Husbandry: No special procedures or breeding practices.{4162}

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SJL/J

Genetics: Derived from Swiss-Webster mice ("Swiss Jim Lambert"){4181}, and develops lymphomas resembling Hodgkin's lymphoma. The tumors are more accurately called type B reticulum-cell sarcomas. The exact genetic basis is unknown. They are also susceptible to induction of experimental allergic encephalomyelitis (EAE) by inoculating with spinal cord homogenate. This susceptibility is dominantly-inherited.

Pathophysiology: Reticulum cell sarcomas are present in 90% of both sexes by 12-13 months. They are mostly of B cell origin.

Husbandry: Become extremely aggressive after 8 weeks of age, so separate males (or treat them with intranasal zinc chloride to keep the olfactory pheromones down). They breed well but only half the pups survive to weaning.{4162}