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Nephrol Dial Transplant. 2002;17 Suppl 9:68-70.

Molecular cloning of a gene for inversion of embryo turning (inv) with cystic kidney.

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  • 1Department of Medicine II, Hokkaido University School of Medicine, Sapporo, Japan.


Vertebrate internal organs of the body develop with a distinctive left-right asymmetry. The mouse inversion of embryonic turning (inv) mutation which was created by random insertional mutagenesis causes a constant reversal of the left-right polarity (situs inversus) as well as cyst formation in the kidney in homozygotes. Since this phenotype is tightly linked to the transgenic integration site, the disrupted gene is likely to be located near this site. To analyse the transgenic integration site, ICRF yeast artificial chromosome (YAC) clones were screened by hybridization with a probe containing this site. Three positive YACs were identified and cosmid libraries were constructed from these. The insertional mutagenesis created a 60 kb genomic deletion on mouse chromosome 4. A cosmid contig spanning the whole deleted region was generated by genomic walking. In an effort to identify transcript(s), we used cosmid insert DNA to screen mouse embryo cDNA libraries directly after pre-competition with Cot1 DNA to suppress the non-specific signal. Only one cDNA clone (3 kb, clone 28) was identified, and we then obtained full-length cDNA. Genomic Southern hybridization indicated that this gene spans the whole deleted region, implying that the homozygous inv mice have an intragenic deletion of this gene. Northern hybridization showed that the gene is expressed as early as embryonic day 7, and its size was approximately 5.6 kb. As the highest expression is seen in kidney and liver in the adult, the expression patterns are consistent with our postulate that the gene is responsible not only for reversal of left-right asymmetry but also for cyst formation in the kidney in the inv mutant. The deduced amino acid sequence shows that the gene has 15 successive repeats of an Ank/Swi6 motif in its N-terminal domain. These repeats are considered to provide a mechanism for recognition of proteins, such as to fix target proteins at certain cellular locations or alter intracellular location of target binding proteins. In conclusion, we have cloned an inv candidate gene that is responsible for both the situs inversus and cyst-forming kidney. The gene product involves ankyrin motif repeats, indicating that a cytoskeleton disruption induces the situs inversus and the cystic kidney.

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