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Abstract: PO1601

Focal Segmental Glomerulosclerosis with Glomerular Basement Membrane Abnormalities Caused by Compound Heterozygous Myosin 1E Gene Mutations

Session Information

Category: Trainee Case Report

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Aiello, Claudia, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Chen, Dhruti P., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Jennette, J. Charles, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Gibson, Keisha L., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Introduction

Nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) in children is often associated with genetic mutations in podocyte structural proteins. This clinical case report highlights a pediatric patient with nephrotic syndrome and FSGS found to have two genetic mutations in myosin 1E gene (MYO1E) encoding the motor domain of the protein. While both of these mutations have previously been identified as variants of unknown significance individually, we report a case of compound heterozygous mutations resulting in FSGS.

Case Description

An 11-year old white male presented with proteinuria and hematuria. Family history of kidney disease included a paternal cousin with hematuria that spontaneously resolved. The patient had no history of recurrent urinary tract infections, kidney stones or excessive NSAID usage. Kidney biopsy revealed FSGS with basket-weaving, splitting and segmental thickening of glomerular basement membranes (GBM) on electron microscopy. Genetic testing was negative for Alport mutations but identified two variants in MYO1E gene (Table). Parental testing revealed each had one variant inherited by the patient, resulting in compound heterozygous mutation in the patient.

Discussion

Both missense mutations in this patient encode the motor domain of myosin 1e protein (residue 19-692), essential for podocyte motility and structural integrity. Hereditary mutations at other locations encoding the motor domain of MYO1E have been described and associated with FSGS. Functional studies showed that MYO1E motor domain variants led to protein mis-localization and disruption to the podocyte structural integrity (Mele et al. NEJM, 2011). MYO1E depletion in mice causes GBM abnormalities similar to lesions in this patient (Chase et al. Am J Physiol Renal Physiol, 2012). While each individual mutation inherited by the patient is not known to be pathogenic, we hypothesize that the combination of non-conservative mutations in the patient resulted in abnormal myosin-1e protein function that caused GBM abnormalities and FSGS.

Genetic diagnostic testing results for proband and parents
 GeneVariant LocationAllelic InheritanceEncoded location of myosin-1e
MotherMYO1E1684 G>A (Gly562Arg)HeterozygousMotor domain, missense mutation
FatherMYO1E275 C>A (Ala92Glu)HeterozygousMotor domain, missense mutation
PatientMYO1E275 C>A (Ala92Glu) and 1684 G>A (Gly562Arg)Double heterozygous2 Motor domain mutations