Atypical focal segmental glomerulosclerosis associated with a new PODXL nonsense variant

Mol Genet Genomic Med. 2021 May;9(5):e1658. doi: 10.1002/mgg3.1658. Epub 2021 Mar 29.

Abstract

Background: Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent.

Methods: We performed exome sequencing on a three-generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy.

Results: The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end-stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein.

Conclusion: This is the first description of a peculiar association combining a PODXL stop-gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy.

Keywords: PODXL; exome sequencing; focal segmental glomerulosclerosis; glomerular basement membrane duplication; membranoproliferative glomerulonephritis; podocalyxin.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Codon, Nonsense*
  • Female
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / metabolism
  • Glomerulosclerosis, Focal Segmental / pathology
  • Humans
  • Kidney / metabolism
  • Kidney / ultrastructure
  • Male
  • Middle Aged
  • Pedigree
  • Sialoglycoproteins / genetics*
  • Sialoglycoproteins / metabolism

Substances

  • Codon, Nonsense
  • Sialoglycoproteins
  • podocalyxin