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Abstract: SA-OR79

Recessive Variants in MYO1C as a Potential Novel Cause of Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic


  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Steroid resistant nephrotic syndrome (SRNS) is the second leading cause of chronic kidney disease in the first three decades of life. The identification of monogenic causes of SRNS has revealed ~60 single-gene etiologies. While in 12-30% of patients with SRNS a causative variant may be detected, many remain without a molecular diagnosis (Sadowski JASN 26:1279, 2015).


To elucidate novel monogenic causes of NS, we performed whole exome sequencing (WES) in an international cohort of 1,382 NS patients.


We identified homozygous missense variants in MYO1C in 2 unrelated children with nephrotic syndrome (c.2273 A>T, p.Lys758Met; c.292C>T, p.Arg98Trp). Myosins including MYO1C are actin-based molecular motors that actively participate in various cellular functions including intracellular trafficking, cell adhesion, motility and maintenance of membrane tension. Podocyte-specific MYO1C knockout shows MYO1C is critical for TGF-β-signaling in podocyte disease pathogenesis (Ehtesham KI 96:139, 2019). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes (Cebrian Development 145:16, 2018). We then performed structural modeling in molecular viewer PyMol using the super function aligning shared regions within both partial structures (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758, R98W), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98W binds to nearby D220 within the Myosin Motor Domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the importance of these variants. Future in vivo knockout and mutagenesis models are required to confirm mutation pathogenicity.


We, here, identified recessive mutations in MYO1C as a potential novel cause of nephrotic syndrome in children.