Pathology
germline mutations in the inversin gene (INVS) (MIM.243305)
Mouse models
The inversion of embryonic turning (inv, murine homolog of human gene INVS) mutant mice present with situs inversus, as well as pancreatic cysts and renal cysts.
The defect in inv mice is caused by mutations in inversin, a gene that is expressed in cells with 9+0 cilia, and includes a subpopulation of embryonic nodal cells, renal epithelia and the retina.
Within the cell, inversin localizes to centrosomes, basal bodies and cilia, as revealed in immunocytochemistry studies and through the characterization of an Inv-GFP fusion protein in transgenic mice.
Once thought to be vestigial organs, it is now becoming clear that cilia represent a specialized region of the cellular membrane that is involved in the interaction with, and sensing of, the extracellular medium to transduce stimuli, which ultimately affect many fundamental biological processes.
It is plausible that proteins such as inversin (INVS), and possibly other ciliary polypeptides, including some of the Bardet-Biedl syndrome (BBS) proteins, could provide a functional signal relay between the cilia, the basal body and the centrosome.
Consistent with this idea, inversin (INVS) binds to the APC2 subunit of the anaphase-promoting complex (APC) and it has been suggested that it is involved in the cell cycle, thereby providing a potential link between ciliary defects and abnormal cell proliferation as the underlying cause of the cystic kidney phenotype of inv mice.
References
O’Toole JF, Otto EA, Frishberg Y, Hildebrandt F. Retinitis pigmentosa and renal failure in a patient with mutations in INVS. Nephrol Dial Transplant. 2006 Jul;21(7):1989-91. PMID: 16522655
Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205. PMID: 15738963
Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet. 2003 Aug;34(4):413-20. PMID: 12872123