Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation.


BACKGROUND: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. METHODS: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. RESULTS: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. CONCLUSIONS: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.





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Publication Info

Phelan, Paul J, Gentzon Hall, Delbert Wigfall, John Foreman, Shashi Nagaraj, Andrew F Malone, Michelle P Winn, David N Howell, et al. (2015). Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation. Clin Kidney J, 8(5). pp. 538–542. 10.1093/ckj/sfv063 Retrieved from

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Gentzon Hall

Assistant Professor of Medicine

My research is focused on defining the molecular underpinnings of podocyte injury and dysfunction in nephrotic syndrome (NS) with a primary focus on focal segmental glomerulosclerosis (FSGS). FSGS is the most common primary glomerular disease that causes end-stage kidney disease in the US and is caused by injury or loss of glomerular visceral epithelial cells (i.e. podocytes). My scientific contributions in the field include the identification of a novel heterozygous missense mutation in Wilms’ Tumor 1 (WT1) that caused non-syndromic familial FSGS (1), the identification of a dominant negative effect of the LIM Homeobox Transcription Factor 1ß R246Q mutation on expression of WT1 (-KTS) isoforms that contributes to the renal-specific phenotype associated with Nail Patella-like Renal Disease (2), and the identification of impaired autophagy and ER stress pathway activation as the cause of podocyte dysfunction and apoptosis induced by the human FSGS-causing ANLN R431C mutation (3). The goal of my research program is to translate novel discoveries in renal genetics into rational therapies and diagnostic tools for patients with NS.


Delbert Raye Wigfall

Professor Emeritus of Pediatrics

My interests are in the diagnosis and treatment of secondary and inflammatory renal diseases, hypertension and general nephrology. I have been involved specifically in the treatment of childhood hypertension, infections, glomerulonephritis, and secondary disease related to sickle cell anemia, and systemic lupus erythematosus. My previous basic training is in the area of complement mediated injury, immune cell aberrancies, and transplant rejection.


John William Foreman

Consulting Professor in the Department of Pediatrics

Dr. Foreman's research interests center on participating in multicenter clinical trials investigating new treatments for hypertension and renal disease.


Shashi Kumar Nagaraj

Professor of Pediatrics

Clinical areas of interest are chronic renal failure, dialysis, transplantation, hypertension, glomerulonephritis, nephrotic syndrome, urinary tract infections, congenital genitourinary anomalies, lupus nephritis,

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