Most animals are born with normal asymmetry of visceral organs (situs solitus), however, reversed asymmetry (situs inversus) has been reported sporadically in a number of species, including mice (Hummel and Chapman, 1959). Two newborn mice were initially observed with milk-filled stomachs on the right rather than on the left side, as would normally be expected. These were offspring of a non-inbred stock of mice homozygous for the mutation known as blebs (symbol my; Hummel and Chapman, 1959). Subsequent breeding studies demonstrated that this trait, situs inversus, was inherited as a single autosomal recessive gene (symbol iv) with incomplete penetrance (Hummel and Chapman, 1959). The situs inversus mutation has been inbred by Dr. Collins and is maintained on the SI/Col strain.
The iv mutation is characterized by left to right transposition of thoracic and visceral organs and the associated vasculature. These include anomalous positions of the postcava, azygos and hepatic portal veins. Abnormalities in position and shape occur with the spleen, liver and lung (Hummel and Chapman, 1959); Sundberg and Collins, 1992). A high frequency (approximately 20%) of heart defects has also been observed arising as the result of defective formation of the cardiac loop (Layton, et al., 1980). Examination of 10-day-old fetuses revealed equal numbers in the shape of a right-handed helix as those in a left-handed helix (Layton, 1976). No other pathologic lesions have been described. The mice are fertile.
No significant microscopic lesions have been described for this mutation. Cilia of sperm tails have been found to be normal in ultrastructural studies (Handel and Kennedy, 1984).
Only 50% of mice homozygous for this mutation exhibit situs inversus while 50% are normal (situs solitus). This observation led to the hypothesis that the normal allele at the iv locus exhibits complete dominance and controls normal visceral symmetry. Loss of this control, in the case of the iv mutation, permits the situs of visceral asymmetry to develop in a random manner (Layton, 1976). The iv locus has been mapped to lie 3 centimorgans proximal to the immunoglobulin heavy-chain constant-region gene complex (Igh-C) on Chromosome 12 (Brueckner, et al., 1989).
Detailed studies of spontaneous diseases, unrelated to situs inversus per se, have not been studied in these colonies.
Kartagener (1933) was the first to recognize a clear association between situs inversus, bronchiectasis and sinusitis in humans. This triad of abnormalities is now known as the Kartagener syndrome and has been shown to be a recessively inherited condition in humans (McKusick, 1988). Affected individuals have abnormal ciliary function of the respiratory epithelium and spermatozoa, resulting in bronchiectasis, sinusitis and infertility. The defect is associated with a lack of the dynein arms of the cilia, which normally would connect the outer doublet microtubules (Afzelius, 1976; Rott, 1979; Torikata, et al., 1991a; Mierau, et al., 1992). This observation led to the hypothesis that normal ciliary function is required for the determination of situs (Afzelius, 1976). The cilia defect has subsequently been found in humans to be present in patients with situs inversus to various degrees. Defective cilia may only be present in respiratory epithelia but no spermatozoa (Jonsson, et al., 1982). In other cases, cilia may have normal ultrastructural features but random orientation, as opposed to the normal, parallel orientation (Rutland and de Iongh, 1990).
Situs inversus, with abnormalities in cilia, has been observed sporadically in dogs. The canine disease appears to be very similar to that described for humans (Edwards, et al., 1983; Hough, et al., 1979).
WIC-Hyd rats develop spontaneous hydrocephalus, half of the male littermates have situs inversus, and the ependymal cilia in these rats are immotile (Torikata, et al., 1991b; Torikata, et al., 1992).
Another mouse mutation (hydrocephalic-polydactyl, symbol hophyp) has immotile cilia but not situs inversus. This mutation is autosomal recessive and located on Chromosome 6. It occurred in irradiated mice. Mutant mice develop hydrocephalus and infertility due to immotile cilia (Hollander, 1976; Bryan, 1983; Green, 1989).
The availability of inbred strains with situs inversus suggests that the cilia defect may be incidental to transposition of organs and not the primary functional defect, although orientation of the cilia has yet to be evaluated. The model provides a controlled test system to study the genes, gene products or exogenous influences responsible for the direction and degree of visceral asymmetry (Collins, 1985).
For example, the iv mouse mutation has been used to genetically reverse the sidedness of drug-induced limb abnormalities (Brown, et al., 1989) and left side predilection of spontaneous testicular teratomas (Stevens, 1982). Furthermore, this mutation provides a tool to study the development of handedness in left-right asymmetry (Brown and Wolpert, 1990; Brown, et al., 1991; Brueckner, et al., 1991).
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