Dartmouth professor of biochemistry Henry Higgs recently helped identify one of the genetic mutations responsible for a deadly inheritable kidney disease. The study, which was co-authored by Higgs and published in Nature Genetics on Dec. 20, was primarily conducted in Boston under the guidance of Martin Pollak, a professor at Harvard Medical School.
The study found that mutations in the INF2 gene are responsible for a form of focal segmental glomerulosclerosis. FSGS is a disease that causes serious scarring through a disruption in the filtration system of the kidneys and is the second leading cause of kidney failure in children, according to The NephCure Foundation, an organization dedicated to research on FSGS and nephrotic syndrome and a sponsor of the study.
Pollak's research team first sequenced the genotypes of two large families with inherited forms of FSGS and found an association between FSGS and a mutation in the INF2 gene in both families. The study found no additional disease-causing mutations in the genotypes of these two families.
The gene affects kidney cells called podocytes, which form a filter between blood and urine that normally prevents proteins from passing into the urine, Higgs said in an interview with The Dartmouth. Mutations in INF2 change the configuration of podocytes, disrupting normal protein filtration.
After the initial discovery of the INF2 mutation, the research group contacted Higgs because they knew he was a specialist in the INF2 gene, Pollak said in an interview.
"[My research team] had been working on this protein called INF2 for four or five years basically just trying to figure out what [INF2] did," Higgs said.
Higgs said he knew that INF2 had some effect on the cytoskeleton a structural component found within individual cells but did not have a particular disease in mind when he began his research.
Pollak said that he had been looking for genes related to FSGS for several years. When Pollak identified INF2 as the site of mutation, Higgs' previous work with the gene provided insight that guided the remainder of the study.
"[Pollak] wouldn't have been able to really get a very good handle on what [INF2] did without our stuff," Higgs said.
In the study, Higgs performed the cloning of the INF2 gene and helped model the effect of the mutations in the gene on the kidney, Pollak said.
The researchers investigated INF2 sequences in 91 other families with FSGS and found INF2 mutations in nine of these families.
"INF2 was sort of a big hit for [Pollak] because he had found 11 families," Higgs said.
In previous studies, Pollak had only found correlations between mutations in genes other than INF2 in seven other families with histories of FSGS.
Because not all 93 families contained the mutated INF2 gene, there are probably many different genes that cause FSGS, Pollak said.
"I think all of these genes [contributing to FSGS] are important," Pollak said, adding that all genes give new insight into how the disease works and which proteins are important in normal kidney functions. "This is a pretty rare form of kidney disease, but it should lead to important insights in kidney studies."
FSGS leads to progressive kidney failure and is fatal unless the patient is treated with dialysis, Pollak said.
The new findings about the INF2 gene may point towards new cures or therapies in the future, Higgs said.
"The most plausible thing is that [INF2] could be used as a diagnostic for people and families where they know that they have a familial FSGS risk," Higgs said. "If you know that you have FSGS ahead of time, you could line up treatments ahead of time."
Still, the new therapies will not come about "overnight," Pollak said.
Further research is required to figure out how exactly the INF2 gene changes the podocyte in the kidney. Pollak and Higgs have already written a joint grant to obtain funding for future research.
"It really opens up for both of us a really cool line of investigation," Higgs said. "It is a good example of how research works, where someone might be studying something without a real disease focus but because of the interactive nature of the business where everyone is publishing and everything is out there, you get this synergistic effect."
