The beige (BgJ) mutation
By John P. Sundberg, DVM, PhD
History of the beige mutation
The name of this mouse mutation represents the color of affected mice in the original description of the beige (bg) mutation that arose at Oak Ridge National Laboratory, as a radiation-induced mutation (Kelley, 1957; Davisson and Lewis, 1990). These mice were on an agouti (A/-) black (B/-) background and exhibited decreased pigmentation of ear, tail and dorsal hair, resulting in the subterminal band being yellow, the middle dark gray, and the base very light gray. The mice had a cafe-au-lait or beige coloration (Witham and Lane, 1991).
A spontaneous remutation, the beige-J (bgJ), arose at The Jackson Laboratory in the C57BL/6J inbred strain. This strain is a non-agouti (a/a), black (B/B) mouse. The result is a dark (charcoal) gray colored affected mouse (Witham and Lane, 1991). This latter mouse, the beige-J, is the mutation commonly used by many scientists today. A second remutation, bg2J, has occurred at The Jackson Laboratory in the C3H/HeJ strain. Dihybrid crosses of congenic parental strains have been used to produce an albino-beige mouse (Robison and Kuwabara, 1978).
The mutant mouse is easily distinguished from heterozygous or wild type controls. The hair is slightly lighter in coloration. Eye color varies from ruby to almost black. Reduced pigmentation is also evident on the ear and tail (Green, 1989). The shade of color may vary on different genetic backgrounds, depending on alleles at other coat color loci that may be carried by the strain. Other gross lesions represent background characteristics of the inbred strain that the mutation is fixed on (such as ophthalmic anomalies on the C57BL/6J background) or infectious diseases secondary to the immunosuppression features of the mutation.
The decrease or dilution of the coloration of hair and other pigmented tissues is due to the reduced number, enlargement and clumping of melanin granules. In normal hair, the pigment granules are numerous and distributed uniformly along the length of the hair shaft. In the beige mouse, the melanosomes are reduced in number and clumped compared to littermate controls (Hearing, et al., 1973). All tissues containing cells with various types of cytoplasmic granules have giant lysosomes. These include granulocytes, lymphocytes, hepatic parenchyma, renal proximal tubules, central nervous system, exocrine and endocrine pancreas, ducts of various glands, thyroid follicles, type II pneumocytes and mast cells (Green, 1989; Oliver and Essner, 1973; 1975). Aging changes include a progressive neurological disorder accompanied by nearly complete loss of Purkinje cells in the cerebellum at a year and a half of age (Murphy and Roths, 1978).
Immunologic and biochemical lesions
A variety of immunological deficiencies or abnormalities associated with the granular defects are well known for the beige mutation. These include defective and reduced bactericidal activity of granulocytes (Gallin, et al., 1974), severe deficiency of natural killer (NK) cells (Roder, 1979), and a defective cytotoxic T-cell and antibody response to allogeneic tumor cells (Carlson, et al., 1984; Saxena, et al., 1982). A variety of lysosomal enzymes are decreased in neutrophils (Takeuchi, et al., 1986). Heterozygotes also have a platelet storage, pool deficiency and serotonin deficiency within the platelets, resulting in prolonged bleeding times (Holland, 1976; Novak, et al., 1981). This can be corrected by bone marrow grafts from normal mice (Novak, et al., 1985).
The inbred strain, C57BL/6J, has a number of known, but poorly documented, pathological anomalies that are often misdiagnosed as infectious diseases or complications of the mutation being studied. Skin lesions include alopecia that occurs around the time of weaning followed by regrowth of hair, adult-onset alopecia, papular dermatitis, and chronic ulcerative dermatitis as the mice age. A variety of ophthalmic anomalies occur that are associated with malformations of the lens in utero. Hydrocephalus occurs with low incidence.
Beige mice have been reported to have a decreased life span when compared to a control group of C57BL/6J mice. The mutants also have lower body weights than controls (Goodrick, 1977).
Because the beige mutation causes specific types of immunodeficiencies, it is not surprising that these mice are more susceptible to infectious diseases. This has been reported for a variety of spontaneous and experimental infections (Lane and Murphy, 1972; Shellam, et al., 1981; Shellam, et al., 1985).
Homologous human disease
Chediak-Higashi syndrome in human beings is essentially identical to the mutant phenotype of the beige mouse (Windhorst and Padgett, 1973; Blume and Wolff, 1972; Hoskin, et al., 1991). In fact, observations on the NK cell deficiency in beige mice led to investigations of human patients for this specific defect, which was then identified (Roder, et al., 1980; Haliotis, et al., 1980).
Homologous animal diseases
Diseases virtually identical to Chediak-Higashi disease of humans have been identified in a variety of domestic and wild animal species including Persian cats (Kramer, et al., 1977), Hereford cattle (Padgett, et al., 1964), Brangus cattle (Ayers, et al., 1988), Aleutian mink (Padgett, et al., 1964), foxes (Nes, et al., 1983; Fagerland, et al., 1987), and killer whales (Taylor and Farrell, 1973).
Common uses for the beige mutation
This mutation is a homologue of the rare human disease Chediak-Higashi syndrome. Methodical study of the mouse mutation has been utilized to identify similar abnormalities in human patients (Roder, et al., 1980; Haliotis, et al., 1980). The beige mutation, often in combination with other mutations such as pale ear (ep), has also been used to study the biology of pigment and pigment genes (Novak, et al., 1980; Novikoff, et al., 1979). The morphologic feature of giant lysosomes has been a useful marker for identifying and studying hematopoietic stem cells (Ash, et al., 1981). The most common use of this mutation, however, is a biomedical tool, utilizing the various immune system abnormalities to study induction and metastatic spread of cancer (Salomon, et al., 1980; Talmadge, et al., 1980; Haliotis, et al., 1985; Carlson, et al., 1984), immunomodulation of infectious diseases (Solomon, et al., 1985; Morahan, et al., 1982; Shellam, et al., 1981; Shellam, et al., 1985), hypersensitivity (Galli and Hammel, 1984); and bone marrow grafts (Harrison and Carlson, 1983; Murphy et al., 1973).
Availability of mice
The beige mutation (alleles bgJ or bg2J) is available as a single mutation on the C57BL/6J or C3H/HeJ inbred strain backgrounds from The Jackson Laboratory. The original bg allele is available in a double mutant with the satin (sa) mutation (McGarry, et al., 1984) on the SB/Le inbred strain. Additional double mutants, including beige and nude (nu) and others may be available occasionally from the research colonies developed and maintained by immunologists on The Jackson Laboratory staff.
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