The gene INVS encodes a protein localized to the primary cilia of the renal epithelium. The Inversin protein, made up of two IQ calmodulin-binding domains and multiple Ankyrin domains, is responsible for the negative regulation of the canonical Wnt signaling pathway. It forms a complex with NEK8, ANKS6 and NPHP3, and it is believed to be involved in renal development as well as left-right axis determination.
The gene is associated with Infantile Nephronophthisis 2, an autosomal recessive disorder characterized by enlarged, hyperechogenic kidneys, chronic tubulointerstitial nephritis, hypertension and eventually renal failure by the age of 3-years.
Located on the long arm of chromosome 9, this gene is 239 kb long and consists of 18 exons. The protein product encoded by the gene has a molecular mass of 117 kDa and is made up of 1065 amino acids. Alternative splicing results in multiple transcripts that encode several distinct isoforms of the INVS protein. Homozygous and compound heterozygous mutations in the INVS gene, such as missense mutations and indels, have been associated with Nephronophthisis 2.
Al-Hamed et al. (2016) carried out a study of antenatal cystic kidney disease in a cohort of 44 Saudi families. Genetic screening of 90 renal genes helped unveil a novel homozygous mutation (c.1760delA, p.Q587Rfs*2) in the INVS gene of one infant. In silico analysis of the novel frameshift mutation by ‘Mutation Taster’ found it to be disease causing. It affects a highly conserved residue and was not found in the ExAC database. The patient, born to consanguineous parents, suffered from enlarged, echogenic kidneys, oligohydramnios/anhydramnios, and ventriculomegaly. The proband had another affected sibling and the case resulted in perinatal death. Genetic analysis found one of the healthy siblings to be heterozygous for the INVS mutation.