Kidney disease

Enemy at the gate

A second gene associated with a heritable form of kidney disease is shown to act as a gatekeeper in primary cilia

Published online Aug 25, 2017

Transverse mouse kidney sections pseudo-colored and arranged in a spiral form

Transverse mouse kidney sections pseudo-colored and arranged in a spiral form

María Rondón Galeano, Institute for Molecular Bioscience, The University of Queensland ©2017 

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.

Polycystic kidney disease (PKD) is a genetic disorder that produces fluid-filled cysts, reducing kidney function and leading to organ failure. Autosomal dominant 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.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology and the Institute of Medical Biology. For more information about the team’s research, please visit the Roy webpage.

Tags: autosomal recessive polycystic kidney diseaseDZIP1Lciliatransition zoneInstitute of Molecular and Cell Biology (IMCB)Institute of Medical Biology (IMB)


  1. Lu, H., Galeano, M. C. R., Ott, E., Kaeslin, G., Kausalya, P. J. et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nature Genetics 49, 1025–1034 (2017).| Article