Mutations in a single gene have long taken sole responsibility for a rare type of kidney disease. Now A*STAR researchers find a second culprit by demonstrating that mutations in another gene also cause the disease.

Autosomal dominant polycystic kidney disease (PKD) is more prevalent and typically affects adults, whereas the rarer autosomal recessive PKD (ARPKD) is more aggressive and affects infants and children. The mortality rate of infants with ARPKD can be as high as 50 per cent and most sufferers need a transplant before their tenth birthday.

Mutations in the gene, polycystic kidney and hepatic disease 1 (PKHD1) were thought to be responsible for ARPKD. Now Sudipto Roy at the A*STAR Institute of Molecular and Cell Biology in Singapore and colleagues demonstrate that ARPKD is also caused by mutations in DAZ interacting protein 1–like (DZIP1L). “Finding that the disease is genetically heterogeneous is surprising,” said Roy.

The authors found that seven patients from four different families carry mutations in DZIP1L. Furthermore, they show that kidney function is compromised in both mice and zebrafish bearing DZIP1L mutations, suggesting that the role of DZIP1L is conserved across the vertebrates.

DZIP1L encodes a protein that localizes to cilia, hair–like structures on cell surfaces, which are vital for kidney cell function. The primary cilium functions as a molecular antenna conveying important messages to the cell about the local environment. Experiments in cells show that DZIP1L localizes to the base of the primary cilium at what is known as the transition zone. This region is important for regulating the transport of proteins in and out of the cilium.

Although the number of cilia is unaffected in DZIP1L mutant tissue, loss of this protein stops two proteins that are important for preventing cyst formation, polycystin–1 and –2, from reaching the primary cilium. As Roy explains, “the ineffective access of polycystin–1 and –2 to cilia could be the cause of cystic kidney disease in patients with mutations in DZIP1L”.

Roy and colleagues also show that DZIP1L interacts with septin2 (SEPT2) to create a diffusion barrier at the transition zone that helps maintain ciliary subcompartments.

The team are now focusing on understanding the mechanism by which DZIP1L functions at the transition zone and determining the extent to which mutations in DZIP1L mutations cause ARPKD. Future research will also investigate therapeutic strategies that facilitate the proper localization of ciliary proteins.