Harvard Catalyst Profiles

We are working to identify genes involved in the development of focal segmental glomerulosclerosis (FSGS). FSGS is a common form of renal disease, seen both as an isolated entity and as a consequence of other primary processes. Towards this goal, blood for DNA extraction and clinical analyses have been performed on members of approximately 125 families with an inherited form of this condition, as well as over a hundred sporadic cases. We identified the first FSGS locus on chromosome 19q13. We have recently found mutations in ACTN4, encoding alpha-actinin-4, as the cause of disease in FSGS-1 linked families. Because FSGS is also a cause of renal dysfunction secondary to multiple other diseases, we are examining the role of this FSGS gene as a candidate renal dysfunction susceptibility gene. Current efforts are also underway to understand the function of ACTN4 and the mechanism of this form of kidney disease. We have developed “knockout” and “knockin” mouse models. We are working to identify additional human FSGS genes by genetic linkage and candidate gene approaches.

A second major focus of study is the extracellular calcium receptor. Previously, I cloned the human calcium-sensing receptor (CaR) gene and demonstrated that CaR defects cause three distinct disorders of extracellular calcium homeostasis. Our current work utilizes mouse models to further define the role of CaR. Mating mice heterozygous CaR "knockout" mice with mice with a targeted disruption of the preproPTH gene generates mice with both mutations. Mice homozygous for both "knockout" alleles, unlike the CaR-deficient mice, are viable because they will be incapable of developing the otherwise lethal hypercalcemia characteristic of CaR-deficient mice. We are using these mice to study the role of CaR in the intestine, in the kidney, as well as in the brain and bone marrow. In addition, we are using Cre/Lox technology to develop tools to allow tissue specific inactivation of CaR.