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Constitutional diseases are here defined as malfunctions or pathological lesions whose etiology depends to a significant degree upon the action of genetic factors. If a disease occurs sporadically among genetically heterogeneous individuals, it may be possible to distinguish between hereditary and environmental influences. The importance of genotype is then not determinable. In genetically controlled laboratory mice, however, it has been possible to identify a wide variety of constitutional diseases. These fall into two general classes, those resulting from action of identified single mutant genes and those with polygenic inheritance ( Chapter 9). These latter conditions appear with different but characteristic frequencies in mice of different inbred strains. Environmental as well as hereditary factors may influence the incidence of conditions in this second genetic class.
We have chosen to omit discussion of prenatal lethal conditions caused by unit gene substitutions and of congenital malformations associated with particular inbred strains ( Chapter 14). We have also omitted all discussion of cancer incidence (Chapters 26, 27), although strain differences in incidences of specific types of neoplasia clearly demonstrate the importance of genetic influences. The abnormal conditions discussed in this chapter are nonneoplastic constitutional diseases present through some part or all of postnatal life. Certain gross structural anomalies are included even though the malfunction responsible for their appearance may be limited to prenatal development.
A clear picture of the spectrum of pathological conditions induced by single genes may be obtained from the concise descriptions of effects associated with each recognized genetic locus ( Chapter 8). Mutants at approximately one-half of the more than 250 named genetic loci in the mouse have effects sufficiently deleterious to be classified as constitutional diseases, many of them congenital. Thirty mutants invariably cause death between birth and maturity, and many others severely reduce viability. Neuromuscular syndromes, severe anemias, gross structural defects, and functional defects of ossification are frequent causes of early postnatal death. Polygenically inherited constitutional diseases are usually but not exclusively degenerative diseases appearing later in life.
Since pathologists are more interested in diseases than in the manner of their inheritance, the conditions to be described, whether dependent on one or many genes, have been combined into groups of related syndromes. These groups are presented in alphabetical order, and within each group all affected mutant genotypes of inbred strains are identified with a brief description of their pathology. The constitutional diseases associated with single-gene substitutions are also presented in Table 29-1. It should be stressed that the condition in each genotype listed is an independent disease, and each may represent a fundamentally different way of producing a particular pathological condition. If the condition or some aspect of its expression is discussed fully in another chapter of this book, we have referred to that source. The amount of information available varies greatly for different conditions and different genotypes. Some of the descriptions in this chapter must therefore be very brief. For two conditions, muscular deformity and the whole group of skeletal disorders controlled by single genes, we have referred to review articles.
AMYLOIDOSIS
Autopsies of certain inbred mice and their hybrids frequently reveal the presence of amyloid deposits, often associated with papillonephritis (the most common kidney disease of the mouse) ( Chapter 26). Amyloidosis develops in a very high percentage of mice in some strains, notably the various sublines of the A strain ( Dunn, 1954) and in SM/J. The incidence of amyloidosis drops in outcrosses of A/He to other strains ( Heston and Deringer, 1948).
West and Murphy ( 1965) analyzed the distribution of amyloid in various organs of A/Sn males at different ages, the relationship of amyloidosis to kidney disease, the histochemistry of amyloid, and its possible association with lymphoid tissue reactions. No amyloid was noted in 1- to 3-month-old A/Sn males, but traces were found in the lungs of 4- to 5-month-old animals. In mice 6 months old and older there was a gradual increase in the number of organs (tongue, heart, skin, liver, testes, urinary bladder, and spleen) involved, as well as in the amount of amyloid present. By the 16th month all of the 15 organs surveyed contained amyloid. Amyloid was always present in the kidney before papillonephritis developed. Except for a consistently negative iodine test, the staining characteristics of amyloid in the mouse are similar to those in man ( West and Murphy, 1965). The pathogenesis of amyloidosis is not entirely known although experimental procedures designed to elucidate it have been numerous (injections of casein, induction of various kinds of immunities, tumor transplantation, parabiosis). Electron microscopic evidence suggests that reticuloendothelial cells are of primary pathogenetic importance ( Heefner and Sorenson, 1962). Histochemical tests demonstrated an increase in the acid mucopolysaccharide content of amyloid deposits of older animals ( Christensen and Rask-Nielen, 1962). Electrophoretic analysis of sera showed that progressive amyloid development is associated with hypergammaglobulinemia, later combined with increases of both β- and α2-globulins.
ANEMIAS
Several different types of hereditary anemias have been reported in the mouse. Hematological features of each anemia are described in Chapter 17. In this chapter we describe the relationship between anemia and viability and the pathological conditions in nonhematopoietic tissues associated with certain of the hereditary anemias.
Reduction of viability is related both to the severity and to the nature of anemia. Mice with extreme hemolytic anemia ( ja/ ja, sph/ sph) are usually born alive but die within 1 to 3 days. During their brief independent existence they develop severe jaundice and may also show cardiac hypertrophy, splenomegaly, and hepatomegaly ( Stevens et al., 1959; Joe et al., 1962). If hemolytic anemia is slightly less severe, a small proportion of the mice ( ha/ ha) or larger proportion of the mice ( mk/ mk) may survive to adulthood.
The survival potentiality of mice with macrocytic anemia depends both on effects of the major anemia-producing genes and upon the genetic background. The period of rapid growth (birth to 5 weeks) is critical, since mice with defects in erythroid maturation have difficulty producing enough erythrocytes to keep pace with their increasing body size. In some stocks all W/ W and an/ an mice are born dead or die within 1 to 3 days ( Russell and Fondal, 1951; Kunze, 1954), but in other specially selected stocks the survival of W/ W or an/ an mice is considerably enhanced ( Russell and Lawson, 1959; Chapter 17). A higher proportion of mice of less severely affected genotypes ( W/ Wv, Wv/ Wv, Sl/ Sld, Sld/ Sld, dm/ dm) ( Chapter 17) survive to adulthood and these have near-normal life expectancy. In mice of certain viable genotypes growth is often impaired, possibly as a nonspecific result of the anemia ( an/ an, dm/ dm, f/ f, sla/ sla) ( Chapter 17).
Some of the pathological lesions associated with particular anemias, but appearing in nonhematopoietic tissues, arise as secondary consequences of specific anemias, but others appear to be independent pleiotropic effects of the action in other tissues of the same genes which affect hematopoiesis. Severe macrocytic anemia is characteristic of mice of all genotypes carrying two dominant W alleles ( Wv/ Wv, W/ Wv) or two dominant Sl alleles ( Sl/ Sld, Sld/ Sld). These mice are also sterile and have black eyes and white hair. For both genic series the sterility has been traced to failure of multiplication of primordial germ cells between the 8th and 12th days of fetal life ( Bennet, 1956; Mintz, 1957; Mintz and Russell, 1957). The lack of hair pigment has been traced to failure of melanoblasts to arrive at the hair follicle sites during fetal development ( Markert and Silvers, 1956) ( Chapter 21). Each of three characteristics effects of W-gene and Sl-gene substitutions appear to result from independent gene action in primarily affected tissues. In 100 per cent of Wv/ Wv, W/ Wv, and Sl/ Sld females, absence of primordial germ cells leads eventually to development of ovarian tumors ( Chapter 27).
Anemic mice of several different genotypes show skeletal abnormalities. Flexed ( f/ f) mice usually show tail flexure through fusion of vertebrae due to anomalies of intravertebral disks, and also show ventral white spotting. These pleiotropic effects may be secondary to fetal anemia ( Kamenoff, 1935). Anemic diminutive mice ( dm/ dm) show abnormalities of the entire axial skeleton ( Stevens and Mackensen, 1958). Skeletal defects of tail-short ( Ts/+) mice are considered by Deol ( 1961) to be secondary effects of a transitory anemia of the primitive cell generation.
Surviving Hertwig's anemic mice ( an/ an) show several abnormalities. Adult an/ an mice of both sexes have fewer definitive germ cells than do normal littermates and seldom produce offspring. The etiology of their sterility is, however, very different from that found in W/ Wv and Wv/ Wv mice. Testicular tubules of newborn an/ an males contain primordial germ cells, but almost no spermatogenesis is seen in adult testes ( Menner, 1957). In one breeding test, three of six 2-month-old an/ an females became pregnant. One which was allowed to come to term produced six offspring, but died shortly after (Wolfe, 1964, personal communication). These findings suggest that an/ an mice, sterility is a secondary effect of anemia, rather than an independent effect upon primordial germ cells. Older an/ an mice (beyond 6 to 8 months) frequently develop eye opacities, lose their hair completely, and become emaciated and kyphotic (McFarland, 1965, personal communication).
A hemolytic anemia of varying severity has been reported as developing in a high proportion of adult mice of the NZB/Bl inbred strain. It appears earlier (6 to 9 months) and more dramatically in males than in females (12 months). Affected mice show reticulocytosis, splenomegaly, jaundice, anemia, and elevated antibody titer ( Helyer and Howie, 1963a). The condition seems to be an autoimmune disease.
The condition did not appear in mice of four other inbred strains in the same colony, nor in the F1 generation of outcrosses, but did appear with considerable frequency in the backcrosses to the NZB/Bl inbred strain, suggesting but not proving a relatively simple inheritance pattern. However, details of expression vary according to genetic background ( Helyer and Howie, 1963b).
The disease regularly has four manifestation: Coombs-positive hemolytic anemia with a variety of hematological, serological, and pathological manifestations: germinal centers in thymic medulla "with variety of secondary changes"; "undue frequency of severe (often lethal) membranous glomerulonephritis"; and positive serological tests for antinuclear factor in a few LE-positive tests ( Burnet and Holmes, 1964; Holmes and Burnet, 1964). Fertility of NZB/Bl females is impaired in certain specific mating combinations, suggesting an autoimmune reaction ( Bielschowsky and Bielschowsky, 1964). The disease shows significant similarities to human autoimmune conditions ( Holmes and Burnet, 1963).
CARDIOVASCULAR DISEASES
In the following presentation, three syndromes will be discussed: dystrophic calcification, which occurs usually in the heart muscle, myocardial fibroplasia of dystrophic mice, and strain-specific arteriosclerosis. A fourth and frequent condition of certain strains, left auricular thrombosis, is considered elsewhere ( Chapter 18).
Dystrophic calcification
Calcerous deposits, mainly involving the pericardium and myocardium, have been observed in a number of inbred strains. A survey revealed heart lesions in almost all retired breeders (more than 10 months old) of strains C3H/J, C3HeB/J, DBA/1J, and DBA/2J; mice of certain other strains, BALB/c and A/J, showed less involvement, and mice of the C57BL/6J, C57BL/10J, C57L/J, RIII/J, 129/J, MA/J, and SWR/J inbred strains had relatively few lesions ( Hummel and Chapman, 1962). These calcium salt deposits are of the type previously reported by Clements ( 1956) as "spontaneous heart disease in DBA/2J mice" and as "calcerous pericarditis" of DBA mice by Hare and Stewart ( 1956). DiPaolo et al. ( 1964) described the lesions as occurring in mice of several related strains, C3H/St, DBA/St, and CHI/St. Although they found similar lesions also in noninbred Swiss mice, the distribution pattern was different in that the deposits also occurred along the epicardium. Importance of hereditary factors to the etiology of calcerous deposits on the heart is thus demonstrated by strain differences, including high incidence in mice from a group of related inbred strains.
Though a genetic susceptibility has been demonstrated, environmental factors also seem to play a role. DiPaolo et al. ( 1962) found that dietary restriction increased the incidence of calcium deposits. Hare and Stewart ( 1956) also thought nutritional deficiency might be important, since in affected animals they invariably observed gastritis related to the amount of roughage contained in the diet. Hummel and Chapman ( 1962) found more extensive muscle fiber damage at younger ages in breeding females of susceptible strains, except in DBA/2J where males also were severely affected. Virgin females were relatively free of lesions.
The pathogenesis of the calcifications is not known. They occur either as multifocal deposits in the myocardium or as diffuse pericardial plaques. In most cases both pericardium and myocardium are involved. These plaques are grossly visible as white specks on the surface of the pericardium or in cross-sections of the myocardium. Microscopically, fiber hyalinization and fibrous (granular tissue, scarring) are usually seen, but never an acute or chronic inflammatory reaction. Bacterial cultures have consistently been negative. The calcification is of the dystrophic type, with normal blood levels of both calcium and phosphorus. It is not possible to conclude whether these lesions are secondary to a metabolic (perhaps localized) aberration ( Dunn, 1954).
Dystrophic calcification may also occur in organs other than the heart; the most frequent sites are the tunica albuginea of the testes and adrenals.
Myocardial fibroplasia
Occasionally cardiac lesions are found in mice of the 129/Re strain afflicted with muscular dystrophy. Involvement of the heart probably occurs in the final stages of the dystrophic process, which has a predilection for the skeletal musculature. The microscopic lesions include edema, vacuolar or hydropic fiber degeneration, pycnosis and karyolysis, sclerosis, myocytolysis, and fibrosis (fibroplasia). The predominant site is the septal region ( Jasmin and Bajusz, 1962).
Vascular diseases
While blood-vascular diseases, both degenerative and inflammatory, are frequent in laboratory animals such as rabbits, rats, and guinea pigs, they are decidedly rare in mice. The absence of vascular lipid deposits and glomerular nodular changes in genetically obese ( ob/ ob) mice is particularly noteworthy, since this mutant is characterized by both hyperglycemia and vastly elevated serum cholesterol levels.
Despite the fact that mice may be subject to a large number of infectious agents, inflammatory lesions are uncommon. Periarteritis nodosa, thought to be the result of a chronic hypersensitivity reaction to an infectious organism, is not observed in mice. This is especially significant because many mouse colonies are chronically infected with bacterial organisms such as Salmonella, pasteurella, etc.
Three types of lesions involving the vascular system have been reported in mice. Two concern single reports. No publications, other than the original description, have recorded similar findings and no definite causes were ascertained. The first syndrome was described as a necrotizing arteritis in strain BL/De mice ( Deringer, 1959) and consisted of amorphous subintimal and medial deposits in arteries and arterioles of a variety of tissues including ovaries (hilum), perirenal adipose tissue, adrenal cortex, uterus, and mesentery. Associated with the deposits were infiltration of the adventitia with lymphocytes and plasma cells. The second condition was a pulmonary phlebitis (and myocarditis) associated with rickettsia-like or coccobacillary-like bodies and polymorphonuclear leukocytes. This disease occurred during blind passages of tissue emulsion from a moribund mouse ( Pappenheimer and Daniels, 1953).
The third type of lesion, arteriosclerosis, is seen quite commonly and consistently in males and females of strain BALB/cJ and SWR/J ( Hummel and Chapman, 1962). Usually it is restricted to the coronary arteries but may involve also the vasa deferentia and mesenteric arteries. It consists of diffuse calcium deposits in the media; neither intima nor adventitia are affected. The cause is unknown.
EYE DEFECTS
Many inherited eye defects are recognized in mice ( Table 29-1; Chapter 8). Several of them are gross structural defects resulting from gene action limited to embryonic development and thus are not pertinent to this chapter. Five mutant genes have been described, however, with postnatal effects on specific tissues of the eye. Dominant cataract ( Cat) leads to liquefaction of the subcapsular zone of the lens. The lens epithelium ruptures in both lens-rupture ( lr/ lr) and ectopic ( ec/ ec) mice. The retinas of adult mice homozygous for rodless (r/r) or retinal degeneration ( rd/ rd) contain no differentiated rods. More extensive descriptions of those anomalies and accounts of experiments analyzing behavior differences associated with them will be found in Chapter 32.
LABYRINTH DEFECTS
Circling behavior, often accompanied by deafness, is one of the most frequently observed inherited disease syndromes in mice; 24 different mutant genes have been described with severe deleterious effects on gross structure or function of the inner ear ( Table 29-1; Chapter 8). Seven of these have been shown to affect the gross structure of the labyrinth, each one interfering in a specific way with inductive relationships. Ten others produce circling and deafness, and three more deafness alone, through degeneration of cells in particular regions of the vestibular apparatus. One gene ( pa/ pa) leads to absence of otoliths. Analysis of behavior differences associated with these syndromes is given in Chapter 32.
LIPID STORAGE DISEASE
An inherited lipid storage disease, foam-cell reticulosis, appeared as a result of spontaneous mutation in CBA/H mice. "In affected homozygotes lipid-containing foam-cells replace the lymphoid tissue of the thymus and Peyer's patches and occur in smaller numbers in other tissues. Investigations suggest that the lipid may be a complex of lysolecithin and cholesterol and the disease is similar to Niemann-Pick disease in man. It is first detectable in mice of 2-3 months" ( Hulse et al., 1965).
MEGACOLON
Innervation of the distal portion of the colon is defective in mice homozygous for either of two nonallelic mutant spotting genes ( ls/ ls and sl/ sl) ( Chapter 8). The absence of ganglia leads to development of megacolon and to death before 6 months. In one piebald ( s/ s) inbred strain (NZY), 10 per cent of the mice developed megacolon at ages ranging from 2 months to 2 years. The association between spotting and incidence of megacolon was even higher in the F2 generation from outcrosses between mice of this inbred strain and solid-colored mice of two other strains (NZB and NZC). Although none of the solid-colored (+/-) offspring developed megacolon, the condition was found in 70 per cent of the spotted ( s/ s) offspring at earlier ages than in the NZY parental stock ( Bielschowsky and Schofield, 1962). A tendency to megacolon has also been observed in a multicolored noninbred stock ( Derrick and St. George-Grambauer, 1957). In all of these spotted mice with megacolon, segments of the gut were aganglionic or at least hypoganglionic. The accumulation of impacted feces apparently results from failure of peristalsis. Thus there is clear evidence of a defect in gut innervation associated with a number of different spotting mutants, and further evidence that this defect leads to megacolon.
MUSCLE DISEASE
Two inherited muscle diseases are known in the mouse: dystrophia muscularis and muscular dysgenesis. Dystrophia muscularis ( dy/ dy), the first hereditarily determined primary myopathy to be identified in an experimental animal, appeared as a deviant in the strain 129/Re ( Michelson et al., 1955). Mice of the genotype dy/ dy, which show pronounced muscle defect with no evidence of central or peripheral neural defect, have been extensively used for many types of research (see Staats, 1965, for references).
Affected animals may be recognized as early as 2 weeks after birth by a characteristic behavior syndrome ( Loosli et al., 1961), including muscular weakness, periodic dragging of the rear feet, clasping of hind limbs when the animal is suspended by the tail, and spasmodic gaping or nodding of the head ( Russell, 1963). In certain stocks segregating for the dystrophy gene, affected animals often show tetanic seizures, but these are not usually fatal. If dystrophic animals live long enough, they develop kyphosis and permanent paralysis of the hind limbs, often with contractures. Dystrophics almost never reproduce naturally. The dystrophic mouse research colony at The Jackson Laboratory is maintained by repeating ovarian transplantations in each generation ( Stevens et al., 1957). Very old dystrophics often develop pneumonia, and renal calculi are common, especially in 129/Re- dy/ dy mice. The lifespan of dystrophics is greatly reduced but varies according to genetic background and diet ( Russell et al., 1962; Coleman and West, 1961).
Tests of the expression of the dy/ dy genotype on a great variety of genetic backgrounds, including five different large F2 populations in addition to a variety of linkage crosses, showed a proportion of recognized dystrophics in each population close to the expected 25 per cent ( Loosli et al., 1961). The clinical symptoms of the dystrophic heterogeneous hybrids resembled those seen in 129/Re- dy/ dy, except for increased vigor and longer lifespans. The dystrophy gene has been transferred to a different homogeneous genetic background (C57BL/6J) by use of the cross-intercross mating system ( Loosli et al., 1961). Lifespans of C57BL/6J- dy/ dy individuals, however, are even shorter than those of 129/Re- dy/ dy individuals on the same regimen ( Russell et al., 1962). For many kinds of experimentation the best animals appear in the F1 hybrid (129/Re- dy/+ x C57BL/6J- dy/+) population, which segregates for especially long-lived, vigorous dystrophic animals and their normal littermates, especially identical except for genes at the dy locus ( Russell et al., 1962). These 129B6F1- dy/ dy dystrophics are easily identifiable by behavior at 2 weeks, are less impaired in their growth than are 129/Re- dy/ dy dystrophics, and have longer lifespans ( Russell et al., 1962).
For many research purposes it is extremely desirable to work with preclinical stages of the dystrophy syndrome, but affected individuals cannot be identified with certainty in these stages in segregating litters. The production of all-dystrophic litters has been achieved by artificial insemination of dystrophic juvenile or young adult females with sperm collected from dystrophic males ( Wolfe and Southard, 1962). Sperm with normal histology and morphology were obtained from the ductus deferens of the 129B6F1- dy/ dy males. Immature 129B6F1- dy/ dy females were subjected to priming doses of pregnant mare serum (PMS) and human chorionic gonadotropin (HCG). After 10 hours they were mated to vasectomized males and received dystrophic sperm by intrauterine injection. The os cervix route has been used since 1964 for insemination ( Southard et al., 1965). This process has been used repeatedly to produce 100 per cent dystrophic litters, with success in approximately one-third of the trials, although it is sometimes necessary to foster the offspring on normal females or even to deliver them by caesarian section.
The histopathology of mouse hereditary muscular dystrophy shows many striking resemblances to that of human muscular dystrophy ( Michelson et al., 1955; Banker and Denny-Brown, 1959; West and Murphy, 1960; Kitiyakara, 1961; Pearce and Walton, 1963; Harman et al., 1963, review and summary), although specific differences have been noted ( Golarz and Bourne, 1960). At 2 weeks when dystrophic mice can first be identified by their behavior, dy/ dy skeletal muscle already shows excessive variation in fiber size, with evidence of both coagulation necrosis and regeneration, nuclear rowing, and increase in connective tissue around the muscle fibers; these defects become more pronounced with advancing age ( Russell, 1963). Electron microscope observations ( Ross et al., 1960) showed swollen mitochondria, swollen vacuolated reticulum, and fragmented myofibrils. Activity and intracellular location of several enzymes in normal and dystrophic muscle have been studied by histochemical methods ( Harman et al., 1963). Studies of the innervation pattern of dystrophic muscle by several methods showed only the "peripheral reactions of intact and healthy nerve fibers to an abnormal and predominantly fragmenting muscle periphery" ( Harman et al., 1963). However, altered miniature end-plate potentials suggest functional and morphological denervation at the myoneural junction ( Conrad and Glaser, 1964).
Although the histological lesions in hereditary muscular dystrophy are similar to those in vitamin E-deficient dystrophy, no vitamin therapy, including treatment with vitamin E ( Tubis et al., 1959) has had any effect on dystrophic mice. There is evidence that administration of certain anabolic androgenic steroids retards progress of the disease, but no suggestion of return of previously lost function as a result of steroid treatment ( Dowben et al., 1964). Dietary improvement greatly increases lifespan of dystrophic mice ( Coleman and West, 1961). At The Jackson Laboratory nutritional muscular dystrophy has been produced in 129/Re-+/+ normal mice by prolonged vitamin E deprivation in order to compare the two diseases on a common genetic background ( Loosli, 1965). Histological lesions were similar in the two diseases, although 129/Re nutritional dystrophy was characterized by late onset, slow progress, and diffuse distribution of lesions. The nutritional disease was rapidly cured by treatment with α-tocopherol. An extremely interesting feature of this experiment was the difference in clinical manifestation of the two conditions. Mice with nutritional dystrophy showed a decrease in muscular strength in both fore- and hind limbs and were unable to hang on to a vertical wire-mesh food hopper. Although dy/ dy mice had little strength in their hind limbs, they could cling to the hopper for some time with their forefeet. The mice with nutritional dystrophy never showed foot-dragging, clasping of the hind limbs when suspended, or spasmodic head-jerking.
Parabiosis experiments, with conjoined normal-dystrophic pairs, indicate clearly there is no circulating factor responsible for muscle breakdown in dy/ dy mice ( Pope and Murphy, 1960; Pope et al., 1964). The stress of parabiosis shortened the life of both normal and dystrophic partners, but there was some suggestion that the progress of dystrophic lesions might be slightly delayed in parabiosed dystrophics, possibly as a result of shared nutrition. Both normal and dystrophic muscle grow successfully in Algire diffusion chambers implanted in histocompatible normal and dystrophic hosts ( O'Steen, 1962). Myoblasts and myotubes appear in implants of normal muscle, and only myoblasts appear, somewhat earlier than normal, in implants of dystrophic muscle. The dystrophy genotype of the recipient has little or no effect on development of the implanted muscle.
Alterations have been found in the physiology of dystrophic muscle that are similar to those in other genetic or induced dystrophies; these include disturbed K-to-Na balance ( Baker et al., 1958; Young et al., 1959; Zierler, 1961), muscular weakness and altered twitch and tetanus tensions ( Brust, 1964). Because of the higher connective tissue content of dystrophic muscle, it is difficult to assess strictly quantitative functional differences. However, qualitative differences have been reported, including heightened excitability and tendency to fibrillation ( Harman et al., 1963). Contraction time of dystrophic muscle is within normal limits, but relaxation is much delayed. In a prolonged series of repeated stimulations, developed tension dropped much more slowly in dystrophic than in normal response. The qualitatively distinct fatigue pattern of dystrophic muscle seems to depend on some basic dissimilarity inherent in the dystrophy myopathy ( Sandow and Brust, 1962; Conrad and Glaser, 1962; McComas and Mossawy, 1965).
The metabolism of dystrophic muscle is disturbed in many ways, including abnormal creatine-to-creatinine balance, deranged lipid, carbohydrate, and protein metabolism, and abnormal levels of a great many enzymes ( Russell, 1963; Harman et al., 1963). Probably many of these alterations are results rather than causes of the basic defect. One promising approach to analysis of the interrelationships of changes is the grouping of enzymes with similar function. In a comparative study of levels in 20 enzymes in dystrophic muscle and in denervated muscle, TPN-requiring enzymes were elevated, DPN-requiring depressed, suggesting "...a shift from normal glycolytic and oxidative pathways to the pentose shunt" ( McCaman, 1963). Hydrolytic and transferring enzymes tend to be elevated. The findings in dystrophic muscle were confirmed and extended by histochemical studies ( Fennell and West, 1963).
In order to determine primary effects a useful approach is that of retrograde analysis, progressing toward earlier stages in an animal's life history, since the cause(s) of dystrophy must be shown to occur prior to the onset of clinical and histological manifestations. Alterations in muscle fibers, including breakdown and regeneration, have been observed in dystrophic mice as early as 3 days after birth ( Laird and Walker, 1964; Platzer and Chase, 1964). Coagulation necrosis has been observed in the tongue, masseter, and psoas musculature of 20- to 21-day 129B6F1- dy/ dy fetuses ( Meier et al., 1965). Elevated adenosinemonophosphatase activity, accumulation of triose phosphates, and higher kidney glycine transamidinase activity which already appear at 2 weeks may be more closely related to the original gene action than other lesions occurring at later stages ( Gould and Coleman, 1961; Chapter 19). The fact that glycine transamidinase levels in dy/+ heterozygotes are intermediate between those observed in +/+ and dy/ dy homozygotes also suggests close relation to primary gene action ( Coleman and Ashworth, 1960).
Gould and Coleman ( 1961) have shown that a ketone body, measured by a method used to determine acetoacetate, accumulates when muscle homogenates from dystrophic mice of all ages and from normal mice under 2 weeks of age are incubated in phosphate buffer fortified with ATP and Mg ions. No such accumulation occurs when muscle homogenates from adult normal mice are incubated under similar conditions. In fact when normal muscle homogenates or ammonium sulfate fractions thereof were added to dystrophic muscle homogenates, accumulation of the ketone body was prevented. A decreased production of pyruvate was also observed in the dystrophic muscle homogenates which accumulated this ketone body. This suggested that the ketone body may in fact not be acetoacetate as originally proposed but rather some intermediate in the glycolysis pathway which is a direct precursor to pyruvate (Coleman, 1965a, 1965b). Reinvestigation of the identity of the ketone established that it consisted mainly of methylglyoxal. The methylglyoxal did not accumulate in dystrophic muscle homogenates but rather resulted from hydrolysis of other compounds, most probably triose phosphates, in the reaction mixture. These triose phosphates accumulate because of decreased activity of the enzymes glyceraldehyde-3-phosphate dehydrogenase and α-glycerophosphate dehydrogenase, which are directly involved in triose utilization and the subsequent production of pyruvate. Glyceraldehyde-3-phosphate dehydrogenase in normal muscle increased rapidly after birth, reaching an adult level at 3 to 4 weeks of age. In contrast, dystrophic muscle exhibits a deficiency as early as 10 days of age at which time further increase in activity stops, causing the deficiency to become progressively more severe. A similar situation was observed in the activity of α-glycerophosphate dehydrogenase. The failure of development of both of these enzymes at the age when dystrophic symptoms become manifest is of particular interest. The decreased activities of these enzymes in dystrophic muscle would effectively block glycolysis thus drastically reducing the energy available to the muscle cell. Also the deficiency of α-glycerophosphate which should result from the decreased activity of α-glycerophosphate dehydrogenase is of special significance in view of the proposed role of this compound as a major source of intramitochondrial energy.
A second and even more severe muscle disease is muscular dysgenesis ( Gluecksohn-Waelsch, 1963) inherited as a unit recessive ( mdg). Homozygous mdg/ mdg mice, which die at birth, are very edematous and show "a severe, general deficiency of skeletal musculature; cardiac and smooth muscles appear normal" ( Pai, 1965a). "The myopathy results from a genetically determined specific interference with skeletal muscle cell differentiation." Abnormalities were first seen in mdg/ mdg fetuses at 13 ¼ days and appeared in any particular muscle "at the time when (its) myoblasts differentiate into striated myotubes, regardless of the embryonic age at which this occurs" ( Pai, 1965b). Mutant skeletal muscle cells never develop into normal fully striated muscle fibers, show no acetylcholinesterase activity at the myoneural junction, and many of them degenerate before birth.
NEUROLOGICAL SYNDROMES
In Table 29-1 we have chosen to separate the mutants often classified as "behavioral" into two groups. The labyrinth mutants which cause circling behavior have already been discussed in this chapter. In this section we will consider mutants with effects in other parts of the nervous system, here called neurological syndromes. Mutations of this second group, leading to convulsive or uncoordinated behavior, have frequently been observed. Some mutants are so severe as to lead to death of the affected homozygotes before weaning age. We have listed first those conditions in which histological studies have demonstrated either myelin degeneration, gross defect of the cerebellum, or degeneration of the dorsal root ganglia of spinal nerves. Certain neuropathological and behavioral anomalies are discussed more extensively in Chapter 32, but it is worth remarking here that degeneration of myelin sheaths may lead both to convulsions ( dl/ dl) and to uncoordinated gait and tremor ( ak/ ak, jp/ jp, wl/ wl). All of the mutants for which cerebellar degeneration has been demonstrated have an abnormal gait and greatly reduced viability. The abnormality of mice with dystonia musculorum ( dt/ dt) is very different, involving a defect of spinal nerves. Histological study of one further condition, trembler ( Tr/+), has failed to disclose pathological lesions in the nervous system ( Chapter 8), and the condition has been listed simply as causing convulsive behavior. The histological basis of the other conditions has not been extensively investigated.
GENETIC OBESITY
In the mouse, mutant genes at three different loci ( ob, ad, and two agouti alleles, Ay and Avy) ( Table 29-1) are known to produce excessive obesity, usually resulting in sterility. In addition, inbred strains of mice differ markedly in their response to the fat content of their dietary regimen. Mice of the inbred strain NZO regularly become extremely obese but remain fertile. Metabolic patterns associated with each of these genetic obesities are described elsewhere ( Chapter 19), and changes in the islets of Langerhans associated with genetic obesity are discussed in Chapter 20. Physiological effects of obesity have been shown to alter incidence and time of appearance of a number of types of neoplasia. Obese mice also have an increased tendency to certain bone diseases ( Sokoloff et al., 1962). Behavioral differences associated with ob/ ob genotype are discussed in Chapter 33.
PITUITARY DWARFISM
The first known case in the mouse of an endocrine abnormality caused by a single-gene mutation was Snell's ( 1929) dwarf. Extensive research using a variety of approaches has demonstrated clearly that all of the defects of dw/ dw mice result ultimately from an anterior pituitary defect (absence of eosinophils and thyrotropes) and lack of growth and thyrotropic hormones. Research on this condition is reviewed in the section on pituitary function ( Chapter 20).
Another type of pituitary dwarf ( df/ df) ( Schaible and Gowen, 1961) shows many similarities to Snell's dwarf, but also some differences in response to hormone therapy ( Chapter 20). Further investigation of this syndrome may provide valuable insight into the interrelationship of cell types in the anterior pituitary.
POLYDIPSIA
Mice from two different inbred strains develop polydipsia-polyuria syndromes for quite different reasons. In 12- to 14-month-old mice, changes in the adrenal, including amyloid deposit and reduction of cortex, lead to a 5- to 10-fold increase in water intake and excretion ( Chapter 20). The pituitaries of these animals are normal, and kidney changes come only after establishment of the polydipsic syndrome. Mice of the MA/J and MA/MyJ inbred strains also show a polydipsia-polyuria syndrome, but this is more probably associated with cysts pressing on the posterior lobe of the pituitary ( Chapter 20). Urine secretion was measured in the "heavy drinkers" and was found to be about equal in amount to water consumed; the urine was light in color, free of sugar, and had a low specific gravity. Since kidneys and adrenals are grossly and histologically normal, abnormal secretion of antidiuretic hormone is suspected ( Hummel, 1960).
Mild diabetes insipidus appears as a pleiotropic effect of the oligosyndactyly ( Os) mutant gene. Certain modifier genes, themselves capable of producing a mild diabetes insipidus, also enhance the manifestation in Os animals. The severe condition associated with Os in the presence of modifying genes is probably renal in origin ( Falconer et al., 1964).
SKELETAL DISORDERS
Inherited skeletal disorders, including both congenital and degenerative diseases, are very common in mice.
Initial malfunction
In a classic presentation of pathological skeletal development, Grüneberg ( 1963) described developmental effects of 39 different mutations in the mouse. Eleven of these are systemic disorders originating in membranes, cartilaginous, or osseous skeleton; eight are systemic disorders imposed upon the skeleton; eight stem from notochord disorder; eight from abnormality of the paraxial mesoderm; eight from abnormal segmentation; and eight as effects limited to the appendicular skeleton ( Table 29-1). Most of these gene actions appear to be limited to embryonic life. In keeping with our emphasis on postnatal disease processes, we will limit discussion to four conditions. The reader is referred to Grüneberg's ( 1963) book for further analysis.
Although the earliest effects of the short-ear gene ( se) can be traced back to defects in precartilaginous condensations, cartilage formation is still defective in young adult se/ se mice, as shown by slow mending of fractured ribs ( Green, 1958). A smaller callus forms, and a smaller quantity of cartilage is produced more slowly.
The disproportionate dwarfism associated with the gene for achondroplasia ( cn) is a true chondrodystrophy, arising from a continuing abnormality in growth of cartilage (Dickie, 1965, personal communication). The shape of almost all bones is changed, and some bones are missing. Histological lesions in cn/ cn cartilage present a "prima facie case of chondrodystrophy" (Grüneberg, personal communication).
The grey-lethal mouse is regarded by Grüneberg ( 1963) as "the prototype of systemic anomaly of the osseous skeleton." Although membranous and cartilaginous skeletons are completely normal, every element of the osseous skeleton is affected through failure of secondary bone resorption ( Bateman, 1954). The ultimate cause of failure or resorption is not known. Grey-lethals have reduced numbers of osteoclasts ( Barnicot, 1947). This finding suggests deficiency of parathyroid hormone in gl/ gl mice, but several experiments ( Barnicot, 1948) have demonstrated parathormone activity in gl/ gl parathyroids ( Chapter 20). Grüneberg ( 1963) suggested that parathormone may be inactivated especially rapidly in gl/ gl mice. Grey-lethals invariably die before 1 month of age, possibly because of malnutrition due to failure of tooth eruption ( Grüneberg, 1935).
A similar but slightly less extreme failure of secondary bone resorption is seen in microphthalmic mice ( mi/ mi), which also usually die before weaning age. Reported investigations of this skeletal defect have been limited to analysis of reshaping of the bone ( Bateman, 1954).
Skeletal abnormalites can be caused by interactions between mother and fetus. Females homozygous for the recessive gene hair-loss ( hl/ hl), when mated to normal ( hl/+ or +/+) males, produce stunted or short-lived hl/+ offspring with bone fractures; their hairless offspring ( hl/ hl) grow normally ( Hollander, 1960). Some demand of hl/+ fetuses must be greater than that of hl/ hl offspring. The mutant hl/ hl mother's metabolism cannot meet this demand.
Osteoarthropathy
Osteoarthropathy of the knee joints occurs in old mice of the STR/1N inbred strain. It may result from an increased growth and vulnerability of cartilage, compounded by mechanical trauma, observed in young STR/1N mice ( Silberberg and Silberberg, 1962). It is genetically controlled, apparently polygenic, and does not occur in progeny of outcrosses to other inbred strains. Genetic studies clearly showed independent inheritance of obesity, which occurs with high frequency in STR/1N, and the susceptibility to degenerative joint disease. Matings between STR/1N and lean AL/N produced F1 hybrids almost as heavy as the STR/1N, with very low incidence of osteoarthropathy ( Sokoloff et al., 1962). Although within the STR/1N strain there was an apparent correlation between plasma cholesterol levels, levels of other lipids, and the predisposition for osteoarthropathy, association between these characteristic disappeared with hybridization.
Experimental induction of obesity by feeding high-fat diets may lead to increased osteoarthritis ( Sokoloff et al., 1960). These changes are secondary to obesity, the increased load borne by the joints being responsible for the development of the disease.
Degenerative joint disease has been recognized in mice of several strains. The knee joint is most commonly involved, demonstrating importance of mechanical influences in pathogenesis. However, different portions of the knee are affected in different strains, and related strains show lesions of similar structures. For example, in related C57/He/N and C57BL/6JN the lateral condyle is involved, whereas in BRSUNT/N, BALB/cAnN and BL/HeN erosion of the patella and intercondylar fossa appeared most commonly. These findings indicated differences in structure of the knee joint among strains. Degenerative joint disease in older age groups is associated with progressive diminution in the number of chondrocytes. Since changes in articular cartilage may or may not be associated with osteoarthritis, the two conditions are not related. Although chondrodystrophy is a generalized degenerative age-induced lesion, osteoarthritis is a localized traumatic or destructive lesion ( Sokoloff, 1956).
Osteoporosis
Osteoporosis occurs in mature obese ( ob/ ob) mice ( Sokoloff et al., 1960; Sokoloff, 1960). Apparently it follows hypercorticism ( Carstensen et al., 1961); similarly the hyperglycemia (obese-hyperglycemic syndrome) is caused by increased production of cortico (gluco-) steroids.
Senile mice of strains C57BL/6, DBA/2, and A/J, 2 years of age or older, suffer from both osteoporosis and osteoarthrosis ( Silberberg and Silberberg, 1962). In general the severity varies among strains, among animals within a strain, and between the sexes. Osteoporosis occurs much more frequently in mice of the DBA strain than in either C57BL/6J or A/J. Osteoarthrosis is more severe and more common in males than in females, whereas the reverse holds for osteoporosis. These sex differences may be related to the action of sex hormones. Indeed, an arthrosis-promoting effect of male sex hormones has been demonstrated in growing male and female C57BL/6 mice. Administration of estrogens during early adulthood, but not later in life, inhibited development of osteoarthrosis. Estrogen may tend to counteract endogenous testosterone and may also have a direct effect on the articular cartilage (Silberberg and Silberberg, 1963a, 1963b).
Ideopathic necrosis
During a survey of spontaneous skeletal disorders in mice, aseptic necrosis of bone was encountered with some frequency. Although mice of a number of strains had lesions, the incidence was especially high (22 per cent) in females of the BL/HeN strains. Certain strains, e.g., AL/N, C57BL/6J, etc., were free of bone lesions. Pathologically, aseptic necrosis resembles such disorders of man as osteochondritis dessicans, aseptic necrosis of epiphyses, and primary types of bone infarcts. The lesions, affecting a number of skeletal structures, often resulted in fracture of the femoral neck, epiphyseal collapse, thoracolumbar kyphosis, or localized osteosclerosis. Because of these complication the animals were severely crippled. On occasion, however, healing took place ( Sokoloff and Habermann, 1958).
The cause is unknown but the condition may be due to arteritis. Although by casual sectioning it was not possible to demonstrate involvement of femoral nutrient vessels, various branches of the iliac artery were frequently affected. In a few serial sections, segments of minute geniculate arteries were found to be completely occluded by fibrous tissue. It may be, therefore, that arterial occlusion resulting from necrotizing arteritis is the cause of the epiphyseal infarction ( Sokoloff, 1959).
DISEASES OF THE UROGENITAL SYSTEM
Abnormalities and malfunctions of the urogenital system occur in mice either as results of the action of unit genes or as polygenically inherited characteristics of particular inbred strains.
Kidney abnormalities induced by single genes
At least six mutant genes ( Table 29-1) in the mouse are known to produce defects in kidney shape and size ( Chapter 8). One example is Short-Danforth ( Sd); homozygotes ( Sd/ Sd) and some heterozygotes ( Sd/+) die shortly after birth because they have no functioning kidney. This defect has been traced to reduced growth of the ureteric buds and failure of induction of the metanephros ( Gluecksohn-Schoenheimer, 1945). Although normal tubules were formed whenever a renal pelvis was induced, recent tissue culture experiments suggest defects in both ureteric and metanephric tissue ( Gluecksohn-Waelsch and Rota, 1963).
Defective kidney function has been demonstrated in mice with urogenital syndrome ( ur/ ur). Gross abnormalities are seen in this genotype on some but not all genetic backgrounds ( Gluecksohn-Waelsch and Kamell, 1955). Even when kidney size is normal almost all ur/ur individuals die within 24 hours after birth. Their kidneys show much lower alkaline phosphatase activity than those of normal littermates. The plasma protein content is lower than that of normal littermates after but not before birth, indicating abnormal water retention. The few surviving mice develop hydronephrosis and polycystic degeneration.
Mice homozygous for kidney disease ( kd) develop nephrosis at the age of 2 to 3 months ( Hulse et al., 1965).
Mice with brain hernia ( bh/ bh) also show abnormal kidney histology and function. Kidneys appear histologically normal at birth, but later develop a polycystic condition ( Bennett, 1959). Chromatographic studies of urine from bh/ bh mice, 0 days to 3 weeks of age, showed pronounced proteinuria and generalized aminoaciduria. No elevation of amino acid content was observed in blood serum, suggesting that the defect is renal in origin. Histological abnormality appears after rather than before abnormal amino acid excretion. Aminoaciduria disappears in polycystic bh/ bh adults, whose urine is unusually dilute.
Urinary calculi
Mice of the 129 strain have a high incidence of urinary calculi. They consist of glycolipoprotein that is different from the organic matrix of crystallized human or bovine calculi. The protein is similar in a general way to the Bence-Jons protein in content of phospholipid, cholesterol, and carbohydrate as well as in high serine level. The 129 strain of mice may be useful for the study of calculus formation ( McGaughey, 1961). The serine content of the total amino acid residue on a weight basis is approximately 15 per cent; the glutamic acid content is also high (about 20 per cent) compared to that of many proteins, and aspartic acid content is low (approximately 5 per cent).
Obstructive uropathy has been a fairly constant observation at necropsy in male STR/1N mice before 16 months of age. Three forms have been observed: cystolithiasis, hemorrhagic occlusion of the urethral sinus, or suppurative vesicourethritis. The lesions develop about hard plugs of altered seminal material impacted in the urethral bulb. The urinary sediment is of mixed type and apparently does not represent a single organic metabolite. Although microorganisms are consistently found in association with the cystolithiasis, it is uncertain whether they are the cause or the result of the urinary stasis. The lesions are genetically determined, do not occur in females, and their development in males is prevented by castration ( Sokoloff and Barile, 1962).
Papillonephritis
Papillonephritis is the most common kidney disease of mice. It consists of multifocal necroses involving the most distal portions of the descending tubules. Nothing is known about its pathogenesis although it occurs in association with amyloidosis ( West and Murphy, 1965). In strain A/Sn mice, amyloid deposits always precede papillonephritis. Papillonephritis represents a primary injury to the renal papilla ( Dunn, 1944).
Glomerulosclerosis
Spontaneous glomerular hyalinization, or glomerulosclerosis, develops in RF mice about 8 to 20 months old ( Gude and Upton, 1960). Its severity progresses with age. Histologically the lesions resemble those observed in mice following irradiation and those associated in man with hypertension, lupus erythematosus, and early diabetes. The glomerular changes are more diffuse than nodular in type and differ therefore from the typical Wilson-Kimmelstiel lesions of diabetes. Earliest lesions are thickening of the capillary wall and luminal dilation; these changes are followed by mesangial cell pycnosis, mesangial hyalinization, and eventually complete fibrosis of the capillary tufts. Originally, amyloidosis was implicated in the pathogenesis of the sclerotic lesions, but extensive histochemical studies suggested the presence of glycolipid, carbohydrate with a 1,2-glycol linkage, collagen, and fibrin. Acid mucopolysaccharides in both ground substance and basement membranes decrease as the disease progresses. Amyloid is entirely lacking ( Gude and Upon, 1962).
Tendency to nephritis in old C57BL/6 mice
In studies of lifespan and incidence of particular types of pathoses in mice from many inbred strains ( Chapter 26), nephritis was observed in 50 to 60 per cent of individuals surviving more than 450 days, in contrast to much lower percentages in most of the other inbred strains. This condition has been described by Dunn ( 1954): "...kidney damage secondary to amyloidosis apparently depends upon the site of deposition in the kidney. ... In strain C57BL, the amyloid was deposited in the glomerulus, the tubules were remarkably well preserved, and the papilla was intact."
SUMMARY
This chapter serves as a guide to the recognized nonneoplastic constitutional diseases of the mouse. These are presented in a classified list arranged alphabetically according to the nature of the disease. The conditions described include those induced by action of specific mutant genes as well as those appearing with characteristic frequency in mice of particular inbred strains. We state the manner of inheritance of each condition when known and discuss certain of the diseases extensively. Cross-references guide the reader to further information about specific diseases.
1The writing of this chapter was supported in part by Public Health Service Research Grants CA 01074-14 and CA 04691-06 from the National Cancer Institute and by a grant from the Muscular Dystrophy Associations of America, Inc.
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Quantitative analysis of the normal and four alternative degrees of an inherited macrocytic anemia in the house mouse.
Blood 6: 892-905.
See also
PubMed.
Russell, E.S., and F.A. Lawson. 1959.
Selection and inbreeding for longevity of a lethal type.
J. Hered. 50: 19-25.
See also
MGI.
Russell, E.S., and E.C. McFarland. 1965. Erythrocyte populations in fetal mice with and without two different hereditary anemias. Fed. Proc. 24: 240 (Abstr.)
Russell, E.S., W.K. Silvers, R. Loosli, H.G. Wolfe, and J.L. Southard. 1962.
New genetically homogeneous background for dystrophic mice and their normal counterparts.
Science 135: 1061-1062.
See also
PubMed.
Sandow, A., and M. Brust. 1962.
Effects of activity on contractions of normal and dystrophic mouse muscles.
Amer. J. Physiol. 202: 815-820.
See also
PubMed.
Schaible, R., and J.W. Gowen. 1961. A new dwarf mouse. Genetics 46: 896. (Abstr.)
Silberberg, M., and R. Silberberg, 1962.
Osteoarthrosis and osteoporosis in senile mice.
Gerontologia 6: 91-101.
See also
MGI.
Silberberg, M., and R. Silberberg. 1963a.
Modifying action of estrogen on the evolution of osteoarthrosis in mice of different ages.
Endocrinology 72: 449-451.
See also
MGI.
Silberberg, M., and R. Silberberg. 1963b.
Role of sex hormone in the pathogenesis of osteoarthrosis of mice.
Lab. Invest. 12: 285-289.
See also
PubMed.
Silberberg, M., and R. Silberberg. 1964.
Dyschondrogenesis and osteoarthritis in mice.
Arch. Pathol. 77: 519-528.
See also
PubMed.
Snell, G.D. 1929.
Dwarf, a new Mendelian recessive character of the house mouse.
Proc. Nat. Acad. Sci. 15: 733-734.
See also
MGI.
Sokoloff, L. 1956.
Natural history of degenerative joint disease in small laboratory animals. 1. Pathologic anatomy of degenerative joint disease in mice.
Arch. Pathol. 62: 118-128.
See also
PubMed.
Sokoloff, L. 1959. Discussion of paper by Deringer. Lab Invest. 8: 1465-1466.
Sokoloff, L. 1960. Comparative pathology of arthritis. Adv. Vet. Sci. 6: 193-250.
Sokoloff, L., and M.F. Barile. 1962.
Obstructive genitourinary disease in male STR/1N mice.
Amer. J. Pathol. 41: 233-246.
See also
PubMed.
Sokoloff, L., L.B. Crittenden, R.S. Yamamoto, and G.E. Jay, Jr. 1962.
The genetics of degenerative joint disease in mice.
Arthritis Rheum. 5: 531-546.
See also
PubMed.
Sokoloff, L., and R.T. Habermann. 1958.
Idiopathic necrosis of bone in small animals.
Arch. Pathol. 65: 323-330.
See also
MGI.
Sokoloff, L., O. Mickelsen, E. Silverstein, G.E. Jay, Jr., and R.S. Yamamoto. 1960.
Experimental obesity and osteoarthritis.
Amer. J. Physiol. 198: 765-770.
See also
PubMed.
Southard, J.L., H.G. Wolfe, and E.S. Russell. 1965.
Artificial insemination of dystrophic mice with mixtures of spermatozoa.
Nature 208: 1126-1127.
See also
PubMed.
Staats, J. 1965. Dystrophia muscularis in the house mouse: a bibliography. Z. Versuchstierk. 6: 56-68.
Stevens, L.C., and J.A. Mackensen. 1958.
The inheritance and expression of a mutation in the mouse affecting blood formation, the axial skeleton, and body size.
J. Hered. 49: 153-160.
See also
MGI.
Stevens, L.C., J.A. Mackensen, and S.E. Bernstein. 1959.
A mutation causing neonatal jaundice in the house mouse.
J. Hered. 50: 35-39.
See also
MGI.
Stevens, L.C., E.S. Russell, and J.L. Southard. 1957.
Evidence on inheritance of muscular dystrophy in an inbred strain of mice using ovarian transplantation.
Proc. Soc. Exp. Biol. Med. 95: 161-164.
See also
PubMed.
Tubis, M., N. Baker, and W.H. Blahd. 1959.
Vitamin therapy in mice with an hereditary myopathy (Dystrophia muscularis).
J. Nutr. 68: 595-601.
See also
PubMed.
West, W.T., and E.D. Murphy. 1960.
Histopathology of hereditary, progressive muscular dystrophy in inbred strain 129 mice.
Anat. Rec. 137: 279-295.
See also
PubMed.
West, W.T., and E.D. Murphy. 1965.
Sequence of deposition and amyloid in strain A mice and relationship to renal disease.
J. Nat. Cancer Inst. 35: 167-174.
See also
PubMed.
Wolfe, H.G., and J.L. Southard. 1962.
Production of all-dystrophic litters of mice by artificial insemination.
Proc. Soc. Exp. Biol. Med. 109: 630-633.
See also
PubMed.
Young, H.L., W. Young, and I.S. Edelman. 1959.
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Amer. J. Physiol. 197: 487-490.
See also
PubMed.
Zierler, K.L. 1961. Potassium flux and further observations on aldolase flux in dystrophic mouse muscle. Bull. Johns Hopkins Hosp. 108: 208-215.
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