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Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis

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Abstract

Background

Pathogenic mutations in the non-muscle single-headed myosin, myosin 1E (Myo1e), are a rare cause of pediatric focal segmental glomerulosclerosis (FSGS). These mutations are biallelic, to date only reported as homozygous variants in consanguineous families. Myo1e regulates the actin cytoskeleton dynamics and cell adhesion, which are especially important for podocyte functions.

Methods

DNA and RNA sequencing were used to identify novel MYO1E variants associated with FSGS. We studied the effects of these variants on the localization of Myo1e in kidney sections. We then analyzed the clinical and histological observations of all known pathogenic MYO1E variants.

Results

We identified a patient compound heterozygote for two novel variants in MYO1E and a patient homozygous for a deletion of exon 19. Computer modeling predicted these variants to be disruptive. In both patients, Myo1e was mislocalized. As a rule, pathogenic MYO1E variants map to the Myo1e motor and neck domain and are most often associated with steroid-resistant nephrotic syndrome in children 1–11 years of age, leading to kidney failure in 4–10 years in a subset of patients. The ultrastructural features are the podocyte damage and striking diffuse and global Alport-like glomerular basement membrane (GBM) abnormalities.

Conclusions

We hypothesize that MYO1E mutations lead to disruption of the function of podocyte contractile actin cables resulting in abnormalities of the podocytes and the GBM and dysfunction of the glomerular filtration barrier. The characteristic clinicopathological data can help to tentatively differentiate this condition from other genetic podocytopathies and Alport syndrome until genetic testing is done.

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Data availability

No datasets were generated that would be necessary to interpret or replicate the findings in this article.

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Acknowledgements

We are grateful to Bjørn Westre, Department of Pathology, Ålesund Hospital, for contributing the first kidney biopsy of patient 2. We are indebted to the late Torunn Fiskerstrand from the Department of Medical Genetics, Haukeland University Hospital, Bergen. Without her, patient 2 would never have been correctly diagnosed. We thank Marie Claire Gubler, Laboratoire d’Anatomie Pathologique, Hopital Necker – Enfants Malades, Paris, for conducting the immunofluorescence investigation of a skin biopsy from patient 2 for collagen IV α chains. We thank Dmitry Lyalin, PhD, co-director of Cytogenetics/Molecular Genetics Laboratory, AHWFBMC, and Alicia Byrne, PhD, Clinical Genome Resource, Broad Institute of MIT and Harvard, for their advice and expert help with variant classification.

Funding

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH under Award R01DK083345 to M.K. and by a pilot research award from the AHWFBMC Department of Pathology to A.M.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, USA

    Mira Krendel & Michael E. Garone

  2. Department of Pathology, Haukeland University Hospital, Bergen, Norway

    Sabine Leh

  3. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Sabine Leh

  4. Department of Pediatrics, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Alcia Edwards-Richards & Jen-Jar Lin

  5. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway

    Damien Brackman

  6. Department of Clinical Science, University of Bergen, Bergen, Norway

    Per Knappskog

  7. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

    Per Knappskog

  8. Department of Pathology, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Alexei Mikhailov

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  1. Mira Krendel
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Correspondence to Alexei Mikhailov.

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The authors declare no competing interests.

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Approved by the Atrium Health Wake Forest Baptist Medical Center Institutional Review Board, ID IRB00063833.

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Krendel, M., Leh, S., Garone, M.E. et al. Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis. Pediatr Nephrol 38, 439–449 (2023). https://doi.org/10.1007/s00467-022-05634-x

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  • DOI: https://doi.org/10.1007/s00467-022-05634-x

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