However, direct evidence showing that
these variants definitively cause kidney disease was lacking because
APOL1 is widely expressed in different cell types but the gene is
present in only some primates and humans. The challenge has been to
create an animal model to prove this.
‘This preclinical study is first proof-of-concept to pave way for development of new therapeutics that target the G1 and G2 mutated APOL1 proteins to reduce kidney disease risk in African Americans.’
Now, a team led by researchers
from the Perelman School of Medicine at the University of Pennsylvania
has engineered mice with these mutations that cause human-like kidney
"The key missing piece has been whether these variants are true
disease culprits," said senior author Katalin Susztak, an
associate professor of Medicine and Genetics, of the study published
online in Nature Medicine
. "Our study established that these mutations are definitely disease causing."
The G1 and G2 APOL1 gene variants, found almost exclusively in
people of West African descent, have been shown to be associated with
two-to-100-fold increased risk of kidney disease development, according
to previous studies. Despite this highly significant risk, more than one
third of African Americans carry the G1 and G2 variants.
surmise that the reason these two mutations are so prevalent is that
they emerged as a result of "positive selection" in people of African
descent because the mutant proteins protect humans against the parasite
that causes African sleeping sickness. Cells that express the G1 and G2
variants of the APOL1 protein are better able to kill these parasites.
To prove that expression of APOL1 with the G1 and G2 mutations
causes kidney disease, the team made mice in which they could induce the
expression of the non-mutated APOL1 gene as well as the G1 or G2
mutated APOL1 genes in different cell types. The team found that when
the G1 and G2 variants are expressed in the filtering cells of the
kidney the disease in the mouse model strongly resembled features of
human kidney disease at the functional, structural, and molecular level.
"These mutant proteins caused the kidney filter to become leaky and
scarred, resulting in defective kidney function" Susztak said.
Kidney disease development was specific to the filtering cells of
the kidney. The scientists found that G1 or G2 mutated APOL1 proteins
interfere with the normal house-cleaning function of the cell, leading
to an accumulation of jumbled proteins, inflammation, and eventually
cell death. This trash removal system is especially important in kidney
filtering cells, as these cells do not renew and losing them results in
scarring of kidney tissue.
"Now that we know that the G1 and G2 mutated APOL1 proteins cause
human-like kidney disease, we can start to look for ways to target them
to reduce kidney disease risk among millions of people of African
descent," Susztak said. "The good news is that in mice the disease
development was experimentally reversible when the G1 and G2 genes were
turned off, and in a related finding, disease severity also correlated
with the amount of expression of G1 and G2 APOL1 variant proteins in