Open AccessAtypical focal segmental glomerulosclerosis associated with a new PODXL nonsense variant
Author(s) -
Marx David,
Caillard Sophie,
Olagne Jérôme,
Moulin Bruno,
Hannedouche Thierry,
Touchard Guy,
Dupuis Arnaud,
Gachet Christian,
Molitor Anne,
Bahram Seiamak,
Carapito Raphael
Publication year - 2021
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1658
Subject(s) - nephrotic syndrome , glomerular basement membrane , focal segmental glomerulosclerosis , podocyte , missense mutation , nephropathy , glomerulonephritis , exome sequencing , medicine , proteinuria , pathology , exome , glomerulosclerosis , nonsense mutation , kidney , biology , genetics , endocrinology , phenotype , gene , diabetes mellitus
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.