Investigation into Novel Gene Mutation Provides Surprising Insights into Rare Kidney Disease

By Katarina Doma

14 March 2019

Picture of a kidney with a pencil pointing to glomerular structures

Advances in genome sequencing technology are bringing personalized medicine one step closer to becoming a reality, and researchers in the Department of Molecular and Cellular Biology are taking the same approach to improve our understanding and treatment of a rare kidney disease.

Congenital Nephrotic Syndrome (CNS) is a serious kidney disease that develops in infants during the first few months of life. Affected children require aggressive treatment, including dialysis and kidney transplants, to survive.  Currently there are over 250 identified genetic mutations of a single gene, NPHS1, that are known to cause the disease.

“Identifying the gene, understanding the gene mutation, then its function and how it impacts the patient is all part of the pipeline of personalized medicine,” says Prof. Nina Jones, a Canada Research Chair who studies cell signalling in kidney disease and other disorders.

The NPHS1 gene is responsible for producing nephrin, a key protein in the kidney’s blood filtration process. Any abnormality in nephrin that affects its function can lead to a range of kidney problems. 

“When this gene is not expressed properly, infants develop CNS. This is how the nephrin protein was first discovered,” says Jones. “But some nephrin mutations also lead to later onset nephrotic syndrome in children and adults”.

Prof. Nina Jones in her lab
Prof. Nina Jones in her lab

Jones and her colleagues were interested in a novel mutation of NPHS1 that was recently discovered in a CNS patient, and how exactly this new mutation affected kidney function.   

The team re-created the mutation in kidney cells in the lab and found that the mutant nephrin protein was “mislocalized” – that is, it was not located where it was needed on the cell surface.    

An additional and unexpected finding from the study may cause scientists to think differently about this disease.

Currently, CNS is known as a recessive genetic disorder, meaning that each parent must pass down a defective copy of the NPHS1 gene for a child to have the disease. However, Jones and her team showed that just one mutated copy of the gene was enough to affect normal function in kidney cells.   

It’s the kind of observation that wouldn’t be possible to test in humans and shows the value of working with cells in the lab, notes Jones.

“What happened in the cells makes us think that we need to reconsider the genetic nature of this disease,” says Jones. “We can no longer think of it as a strictly recessive effect of the mutation.”

Jones notes that inheriting just one mutated copy of the protein could lead to “intermediate” disease effects, such as predisposing an individual to kidney disease later in life. However, more research will be needed to tease out these subtle impacts.

In addition to challenging our understanding of the genetics of nephrotic syndrome, the study marks a valuable contribution to our knowledge of NPHS1 mutations and their effects on protein function.  In a world where personalized medicine will soon become the norm, such knowledge can help to determine if targeted therapies are an option for patients with kidney disease.


This study was funded by a Tier II Canada Research Chair in Eukaryotic Cellular Signalling and a KRESCENT New Investigator Award from CIHR/ Kidney.


Read the full study in the journal PLOS One.

Read about other CBS Research Highlights.