title: Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis.
abstract: Our understanding of focal and segmental glomerulosclerosis (FSGS) has advanced significantly from the studies of rare, monogenic forms of the disease. These studies have demonstrated the critical roles of multiple aspects of podocyte function in maintaining glomerular function. A substantial body of research has suggested that the integral membrane protein podocalyxin (PODXL) is required for proper functioning of podocytes, possibly by preserving the patency of the slit diaphragm by negative charge-based repulsion. Exome sequencing of affected cousins from an autosomal dominant pedigree with FSGS identified a cosegregating private variant, PODXL p.L442R, affecting the transmembrane region of the protein. Of the remaining 11 shared gene variants, two segregated with disease, but their gene products were not detected in the glomerulus. In comparison with wild type, this disease-segregating PODXL variant facilitated dimerization. By contrast, this change does not alter protein stability, extracellular domain glycosylation, cell surface expression, global subcellular localization, or interaction with its intracellular binding partner ezrin. Thus, a variant form of PODXL remains the most likely candidate causing FSGS in one family with autosomal dominant inheritance, but its full effect on protein function remains unknown. Our work highlights the challenge faced in the clinical interpretation of whole-exome data for small pedigrees with autosomal dominant diseases.
authors.affiliation: 1] Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Moumita
authors.initials: M
authors.lastname: Barua
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Shieh
authors.affiliation: 1] Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schlondorff
authors.affiliation: 1] Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA [2] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Philadelphia, USA.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Kaplan
authors.affiliation: 1] Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D004285:Dogs; D059472:Exome / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D014644:Genetic Variation; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008875:Middle Aged; D011817:Rabbits; D051381:Rats; D017422:Sequence Analysis, DNA; D012795:Sialoglycoproteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D012795:Sialoglycoproteins; C001643:podocalyxin
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