OUR projects
OUR RESEARCH
We are interested in identifying and understanding genes important in kidney disease and kidney function. We have a particular interest in digging into the mechanisms by which mutations in several specific genes: ACTN4, a gene which encodes a protein important in the structure in the cytoskeleton of certain kidney cells; INF2, which encodes a member of the formin family of actin-regulating proteins; and APOL1, an apolipoprotein component of high-density lipoprotein (HDL). Two commons protein-altering variants in APOL1 explain much of the increased risk for FSGS and other forms of non-diabetic kidney disease seen with high frequency among people of recent African ancestry. We continue to investigate these and other proteins by a variety of methods.
APOL1 MEDIATED Kidney disease
Kidney disease is much more common in African Americans than in other racial and ethnic groups. The large disparity in kidney disease rates between white and black individuals has both genetic and environmental components. We and our many collaborators demonstrated that two specific genetic variants in the APOL1 gene on chromosome 22 are the causal drivers of this large difference in kidney disease risk. These two variants encode amino acid changes that alter the function of Apolipoprotein-L1 (or ApoL1). The more common risk allele, G1, encodes two amino acid substitutions near the C-terminus of the protein that almost always occur together. The second risk allele, G2, is a two amino acid (6 base pair) deletion immediately adjacent to the location of the G1 allele. These two risk alleles are never found on the same chromosome. Two risk alleles are required for these large increases in risk, whereas a single allele has at most minimal effects, consistent with a recessive mode of inheritance. With allele frequencies in African Americans of 23% and 15%, respectively, G1 and G2 are among the most powerful common genetic risk variants discovered to date for any phenotype. These initial observations have now been widely replicated. All our work on APOL1 is done in close collaboration with David Friedman's lab, also at BIDMC and HMS.
INF2 MUTATIONS ANd disease
Mutations in INF2, or Inverted Formin 2, lead to kidney disease characterized by proteinuria, progressive kidney dysfunction, and focal and segmental glomerulosclerosis (FSGS). Nine to 17 percent of familial FSGS patients have INF2 mutations, making it among the most common autosomal dominant forms of this disease. Over 50 independent disease-causing mutations have been reported to date, with many of these mutations reported multiple times in unrelated families. A subset of people with INF2-mediated FSGS also exhibit the demyelinating neuropathy Charcot Marie Tooth disease (CMT).
INF2, or Inverted Formin 2, is a member of the 15 member formin family of actin binding proteins. Formins promote actin filament assembly by three mechanisms: 1) accelerating filament nucleation; 2) accelerating filament elongation; and 3) blocking filament capping. INF2 exists as two major splice isoforms, one with a CAAX motif that is targeted to the ER, and a non-CAAX form that is cytoplasmic. The CAAX isoform mediates mitochondrial fission, through two independent mechanisms: increasing ER-to-mitochondria calcium exchange and recruitment of a dynamin GTPase Drp1. The non-CAAX isoform helps maintain Golgi integrity, and plays roles in vesicle transport. We are interested in gaining a better understanding of INF2-mediated disease.
ACTN4, FSGS, and GLomerular function
Mutations in ACTN4, encoding alpha-actinin-4, cause a form of autosomal dominant kidney disease characterized by FSGS histology. ACTN4 is an actin binding and cross-linking protein. actin binding activity in the mutant protein. Current studies are focusing on the function of ACTN4 and the mechanism of this form of kidney disease using mouse models, cell biologic, and biophysical approaches. Our recent evidence suggests that mutations, stress, and phosphorylation regulate exposure of a normally hidden actin-binding site.
Figure: Top panels: Kidney histology in a new CRISPR S159D knockin mouse model. PAS stained kidneys shown from a 10 week old Actn4 S159D mouse (left) and a littermate control of the same age. The glomeruli from the S159D Actn4 mice show significant matrix accumulation and loss of normal open glomerular capillaries. The S159D mice also had significant proteinuria, not seen in control mice. Lower panels: EM pictures from same animals. S159D glomeruli show extensive podocyte foot process abnormalities.