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Kidney Week

Abstract: SA-PO1175

Recessive Mutations in TLN1 Are a Potential Novel Cause of Nephrotic Syndrome in Humans

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


Group or Team Name

  • Roxanna Fouladi. Harvard University, Cambridge, MA.

Nephrotic syndrome (NS) is characterized by a significant loss of protein in the urine causing hypoalbuminemia and edema. NS is categorized into steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS). Steroid resistant nephrotic syndrome is the second most common cause of chronic kidney disease in the first three decades of life. Mutations in over 59 genes provide a monogenic cause in up to 29.5% of NS cases (JASN 26:1279, 2015). This implies that novel genetic and mechanistic causes of NS may explain some of the currently undiagnosed ~70% of cases. The mechanisms of steroid action in SSNS are still unknown and treatment options for SRNS are limited.


To identify additional monogenic causes of NS we performed whole exome sequencing in >2,000 individuals with NS. We identified a homozygous TLN1 mutation in B3328-21 (c.5964_5966del, I1989del). We screened an additional cohort of 605 patients with NS with a Fluidigm Access ArrayTM for TLN1 mutations and identified a compound heterozygous mutation in patient A3788-21 with SSNS (c.235A>G, M79V and c.3491G>C, S1164T).


TLN1 encodes a protein that binds to and activates integrins, coupling them to the actin cytoskeleton (FEBS Letters; 592:2108, 2018). Podocytespecific Tln1 knock out mice have been described to develop an altered podocyte cytoskeleton structure, proteinuria, focal segmental glomerulosclerosis, and die at the age of 10 weeks likely due to renal failure (JCI 124:1098, 2014).


In conclusion, we have identified mutations of TLN1 as a potential novel cause of nephrotic syndrome.