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Human genetics

Flushing out the connections

Nature Reviews Genetics volume 4, pages 674–675 (2003)Cite this article

Last year, NPHP1 and NPHP4 were implicated in NPHP1 and NPHP4, respectively. Although these loci were mapped by positional cloning, Otto et al. opted for a candidate approach in their search for a locus associated with NPHP2. This was because a specific interval on chromosome 9 had already been implicated in NPHP2 and, importantly, the INVS gene — an orthologue of mouse inv — lies in this interval. Mouse inv/inv mutants have a kidney phenotype that is reminiscent of NPHP and, interestingly, of PKD. This phenotypic similarity proved to be a valuable clue — in seven affected families the authors found nine distinct recessive mutations in INVS, seven of which were truncations and two that were missense mutations. As the seven truncations remove different domains of inversin, only some individuals also showed situs inversus — randomization of left/right body asymmetry.

NPHP1 and NPHP4 encode nephrocystin and nephrocystin-4, respectively, which physically interact with each other. Otto et al. showed that inversin also interacts with nephrocystin in vivo and in vitro. Immunoprecipitation of tagged nephrocystin showed that β-tubulin, which is a component of primary cilia in kidney cells, is also part of this complex. It turns out that nephrocystin and inversin are expressed in primary cilia too.

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References

ORIGINAL RESEARCH PAPERS

  1. Otto, E. A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left–right axis determination. Nature Genet. 20 July 2003 (10.1038/ng1217)

  2. Olbrich, H. et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nature Genet. 20 July 2003 (10.1038/ng1216)

FURTHER READING

  1. Vainio, S. & Lin, Y. Coordinating early kidney development: lessons from gene targetting. Nature Rev. Genet. 3, 533–543 (2002)

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Authors
  1. Magdalena Skipper
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Skipper, M. Flushing out the connections. Nat Rev Genet 4, 674–675 (2003). https://doi.org/10.1038/nrg1171

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