Cloning of inv, a gene that controls left/right asymmetry and kidney development

Abstract

Most vertebrate internal organs show a distinctive left/right asymmetry. The inv (inversion of embryonic turning) mutation in mice was created previously by random insertional mutagenesis; it produces both a constant reversal of left/right polarity (situs inversus) and cyst formation in the kidneys. Asymmetric expression patterns of the genes nodal and lefty are reversed in the inv mutant, indicating that inv may act early in left/right determination. Here we identify a new gene located at the inv locus. The encoded protein contains 15 consecutive repeats of an Ank/Swi6 motif at its amino terminus. Expression of the gene is the highest in the kidneys and liver among adult tissues, and is seen in presomite-stage embryos. Analysis of the transgenic genome and the structure of the candidate gene indicate that the candidate gene is the only gene that is disrupted in inv mutants. Transgenic introduction of a minigene encoding the candidate protein restores normal left/right asymmetry and kidney development in the inv mutant, confirming the identity of the candidate gene.

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

“…In individuals with NPHP2, in whom we detected recessive mutations in INVS, the renal phenotype was similar to that described for inv/inv mice 18,19 . In one of the nine individuals with mutations in INVS, there was complete situs inversus.…”

“…The link between inversin, polycystin-1 and polycystin-2, the cell cycle and calcium signaling was suggested to lie in a function of primary cilia as an environmental sensor for the centrosome, thus regulating the cell cycle 23 . The relationship between genes involved in renal cystic diseases and their functional expression in primary cilia is of interest in the light of the finding that taxol, a compound that promotes microtubule assembly, inhibited PKD progression in cpk mice 36,37 .In individuals with NPHP2, in whom we detected recessive mutations in INVS, the renal phenotype was similar to that described for inv/inv mice 18,19 . In one of the nine individuals with mutations in INVS, there was complete situs inversus.…”

“…The homozygous truncating mutation in individual A8 would be analogous in severity to the molecular defect of the inv/inv mouse, in which exons 3-11 were homozygously deleted and in which situs inversus was present in 90% of mice 18,19 . Thus, we confirmed in humans the role of inversin for left-right axis specification that has been described in mice 18,19 .Recently, it has become apparent that products of other genes associated with renal cystic disease (in addition to inversin) are important in left-right axis determination of the body plan 20,39 . The gene PKD2, mutations in which cause autosomal dominant PKD and which encodes the calcium release channel polycystin-2, had been shown in a Pkd2 −/− mouse model to represent a master gene regulating left-right axis determination, acting upstream of Nodal, Ebaf, Leftb and Pitx2 (ref.…”

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

“…INVS mutations result in NPHP2, an autosomal recessive cystic kidney disease, which leads to severe kidney failure in early childhood (Otto et al , 2003; Tory et al , 2009; Oud et al , 2014). Consistent with the phenotype of Inv −/− mice, an animal model for NPHP2 (Mochizuki et al , 1998; Morgan et al , 2002b; Eley et al , 2004), INVS knockdown by antisense morpholino oligonucleotides causes pronephric cysts in zebra fish (Simons et al , 2005). …”

“…In this study, Inversin (INVS), a ciliary protein with highly conserved ankyrin repeats and IQ domains, was found to specifically bind both Akt2 and Akt3 by yeast two‐hybrid screening (Mochizuki et al , 1998; Morgan et al , 2002b; Eley et al , 2004). Mutations in the INVS gene result in nephronophthisis type II (NPHP2), an autosomal recessive cystic kidney disease that progresses to end‐stage renal failure during early infancy and is occasionally associated with situs inversus (Otto et al , 2003; Saunier et al , 2005; Badano et al , 2006; Gerdes et al , 2009; Tory et al , 2009).…”