Nephronophthisis and GLIS2

Cystic kidney diseases

Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of end-stage renal failure in the first three decades of life.

It has been found that most proteins mutated in cystic kidney diseases of human and animal models are expressed in primary cilia or centrosomes of renal epithelial cells, contributing to the theory that states that cystic kidney diseases are "ciliopathies“.

GLIS2 (and GLIS3) localize to the primary cilia

The GLIS2 gene, which encodes a Kruppel-like zinc finger transcription factor, is most abundantly expressed in the adult kidney.

Both GLIS2 and GLIS3 localize to the primary cilia.

NPHP-like phenotype caused by GLIS2 mutation in mice

In the past, we were able to identify GLIS2 mutations as a cause for nephronophthisis in humans. This is based on our observations in GLIS2 knock out mice that show severe renal atrophy and fibrosis starting at 8 weeks of age (Attanasio et al., Nat Genet, 2007).

In the future, it will be crucial to understand the regulation of the cilia signal tranducers GLIS1-3, because this might allow for the development of drugs that can modulate this pathway. This will have implications for many human ciliopathies that are caused by malfunction of this organelle, e.g. the Bardet-Biedel syndrome.