| Popis: |
Studies of rare monogenetic forms of the glomerular kidney disease focal segmental glomerulosclerosis (FSGS) have highlighted the importance of the podocyte in glomerular filtration. Recent reports have also demonstrated that the integral membrane protein podocalyxin (PODXL) is essential for the proper functioning of podocytes, possibly through maintaining the patency of the filtration slits by virtue of charge repulsion. Through whole exome sequencing, our group has recently identified rare co-segregating variants in PODXL in several families with autosomal dominant FSGS. One of the private variants, p.L442R, changes a highly-conserved non-polar residue into a charged residue within the protein’s transmembrane domain. Using biochemical and cell-based assays, we demonstrate that the private variant enhances dimerization of the protein. However, the variant does not alter PODXL protein stability, subcellular localization, glycosylation, or interaction with known binding partner ezrin. Our data suggests that the variant is the most likely cause of disease in one family with autosomal dominant FSGS. However, the pathogenicity of the PODXL variant remains unclear, illustrating the challenges of confirming or refuting a rare mutation as disease causing. |
