JAX Notes January 01, 1993

The situs inversus iv mutation

History

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.

Gross lesions

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.

Microscopic lesions

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).

Genetics

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).

Background lesions

Detailed studies of spontaneous diseases, unrelated to situs inversus per se, have not been studied in these colonies.

Homologous human disease

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).

Homologous animal disease

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).

Common uses for the situs inversus mutation

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).

References

1. Afzelius BA. A human syndrome caused by immotile cilia. Science 193:317-319, 1976.

2. Brown NA, Hoyle CI, McCarthy A, Wolpert L. The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice. Development 107:637-642, 1989.

3. Brown NA, McCarthy A, Wolpert L. Development of handed body asymmetry in mammals. In: Biological Asymmetry and Handedness. Bock GR, Marsh J (eds.), John Wiley & Sons, Chichester, pp. 182-201, 1991.

4. Brown NA, Wolpert L. The development of handedness in left-right asymmetry. Development 109:1-9, 1990.

5. Brueckner M, D'Eustachio P, Horwich AL. Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera. Proc Natl Acad Sci USA 86:5035-5038, 1989.

6. Brueckner M, McGrath J, D'Eustachio P, Horwich AL. Establishment of left-right asymmetry in vertebrates: genetically distinct steps are involved. In: Biological Asymmetry and Handedness. Bock GR, Marsh J (eds.), John Wiley & Sons, Chichester pp. 202-218, 1991.

7. Bryan JHD. Abnormal cilia in male-sterile mutant mouse. Virchows Arch 400:77-86, 1983.

8. Collins RL. On the inheritance of direction and degree of asymmetry. In: Cerebral Lateralization in Nonhuman Species. Glick SD, ed., Academic Press, New York, pp. 41-71, 1985.

9. Edwards DF, Patton CS, Bemis DA, Kennedy JR, Selcer BA. Immotile cilia syndrome in three dogs from a litter. J Am Vet Med Assoc 183: 667-672, 1983.

10. Green MC. Catalog of mutant genes and polymorphic loci. In: Genetic Variants and Strains of the Laboratory Mouse. 2nd ed., Lyons MF, Searle AG (eds)., Oxford Univ Press, Oxford, pp. 12-403, 1989.

11. Handel MA, Kennedy JR. Situs inversus in homozygous mice without immotile cilia. J Hered 75:498, 1984.

12. Hollander WF. Hydrocephalic-polydactyl, a recessive pleiotropic mutant in the mouse, and its location on chromosome 6. Iowa State J Res 51:13-23, 1976.

13. Hough JD, Carlson B, Weitkamp RA, McLean RT. Situs inversus and intussusception in a dog. J Am Anim Hosp Assoc 15:335-337, 1979.

14. Hummel KP, Chapman DB. Visceral inversion and associated anomalies in the mouse. J Hered 50:9-13, 1959.

15. Jonsson MS, McCormick JR, Gillies CG, Gondos B. Kartagener's syndrome with motile spermatozoa. N Engl J Med 307:1131-1133, 1982.

16. Kartagener M. Zur Pathogenese der Bronchiektasien. Bronchiektasien bei Situs viscerum inversus. Beitr Klin Tuber 83:489-501, 1933.

17. Layton WM. Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse. J Hered 67:336-338, 1976.

18. Layton WM, Manasek FJ. Cardiac looping in early iv/iv mouse embryos. In: Etiology and Morphogenesis of Congenital Heart Disease. Van Praagh R, Takao A, eds., Futura, New York, pp. 109-126, 1980.

19. McKusick VA. Mendelian Inheritance in Man. 8th ed., Johns Hopkins Univ. Press, Baltimore, 1988.

20. Mierau GW, Agostini R, Beals TF, Carlen B, Dardick I, Henderson DW, Pysher TJ, Weeks DA, Yowell RL. The role of electron microscopy in evaluating ciliary dysfunction: report of a workshop. Ultrastruct Pathol 16:245-254, 1992.

21. Rott HD. Kartagener's syndrome and the syndrome of immotile cilia. Hum Genet 46:249-261, 1979.

22. Rutland J, de Iongh RU. Random ciliary orientation. A cause of respiratory tract disease. N Engl J Med 323:1681-1684, 1990.

23. Stevens LC. Genetic influences on teratocarcinogenesis in mice. In: Genetic Approaches to Developmental Neurobiology. Tsukada Y, ed., Tokyo, Univ Tokyo Press, Tokyo, pp. 87-94, 1982.

24. Sundberg JP, Collins RL. Animal models of human disease: situs inversus. Comp Pathol Bull 24:2,6, 1992.

25. Torikata C, Kawai T, Nogawa S, Ikeda K, Shimizu K, Kijimoto C. Nine Japanese patients with immotile-dyskinetic cilia syndrome: an ultrastructural study using tannic acid-containing fixation. Hum Pathol 22:830-836, 1991a.

26. Torikata C, Kijimoto C, Koto M. Ultrastructure of respiratory cilia of WIC-Hyd male rats. An animal model for human immotile cilia syndrome. Am J Pathol 138:341-347, 1991b.

27. Torikata C, Koto M, Miwa M. Immotile cilia syndrome in rats. Comp Pathol Bull 24:3-4, 1992.