Kidney Week

Abstract: SA-PO627

The Novel MYH9 Variant, c.1270C>G, p.Arg424Gly, Causes Epstein-Fechtner Syndrome by the Modification of Nonmuscular Myosin IIA Contraction

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Pollinger, Lena, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Lena Pollinger, MSc

• Greve, Johannes N., Institute for Biophysical Chemistry, Fritz-Hartmann-Centre for Medical Research, Hannover Medical School, Hannover, Germany

Johannes N. Greve, PhD

• Kaliman, Sara, Max-Planck-Institut fur die Physik des Lichts, Erlangen, Bayern, Germany

Sara Kaliman, PhD

• Abuhattum, Shada, Max-Planck-Institut fur die Physik des Lichts, Erlangen, Bayern, Germany

Shada Abuhattum, PhD

• Kräter, Martin, Max-Planck-Institut fur die Physik des Lichts, Erlangen, Bayern, Germany

Martin Kräter

• Wiesener, Antje, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Antje Wiesener, DrMed

• Pasutto, Francesca, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Francesca Pasutto, PhD

• Grosch, Melanie, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Melanie Grosch, PhD

• Haak, Jan René, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Jan René Haak, MSc

• Kolb, Cathiana, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Cathiana Kolb

• Daniel, Christoph, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Christoph Daniel, PhD

• Amann, Kerstin U., Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Kerstin U. Amann, MD

• Schiffer, Mario, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Mario Schiffer, MD, DrMed, MBA

• Manstein, Dietmar J., Institute for Biophysical Chemistry, Fritz-Hartmann-Centre for Medical Research, Hannover Medical School, Hannover, Germany

Dietmar J. Manstein, PhD

• Wiesener, Michael Sean, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Michael Sean Wiesener, MD, DrMed

• Jobst-Schwan, Tilman, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

Tilman Jobst-Schwan, DrMed, MD

Background

The MYH9 gene encodes the heavy chain of non-muscular myosin IIA (NMMIIA). Mutations in MYH9 cause autosomal-dominant monogenic disorders that include macrothrombocytopenia, proteinuric kidney disease and elevated liver enzymes.

Methods

Whole exome sequencing was performed in a patient with end-stage renal disease. Segregation analysis in all affected family members was done by Sanger sequencing. Patient tissue biopsies were analyzed. Primary skin fibroblasts were used in migration assays. Immortalized human podocytes were transfected and stained for NMMIIA. Blood smears were inspected by light microscopy and stained for NMMIIA. Blood cell deformability was analyzed by microfluidic technique. Functional analysis of recombinant protein was performed using in vitro motility assays.

Results

We identified the putative deleterious MYH9 variant c.1270C>G, p.Arg424Gly (ACMG class 4, CADD score 22, evolutionary highly conserved), heterozygous in 5 affected family members. The variant affects the O-helix in the upper 50k subdomain of the motor domain, which contributes to the conformational coupling between the actin binding site, the nucleotide binding site and the lever arm region. All 5 patients presented with proteinuria, elevated liver enzymes and intermittent thrombocytopenia. No Döhle-like bodies and NMMIIA-positive conglomerates were found in granulocytes. However, granulocytes had modified deformability compared to healthy controls. Patient skin fibroblasts showed elongated morphology and reduced surface area. MYH9 c.1270C>G transfected immortalized human podocytes displayed NMMIIA -positive conglomerates. Further functional assays revealed a 22% increase in motility at molecular level compared to wild-type protein.

Conclusion

We identified a novel variant in the MYH9 gene in a family with hepato-renal disease as the major phenotype of the intrafamilial syndrome. Functional data confirmed the predicted pathogenicity of this variant by identifying altered mechanical properties and highlighted the multicellular function of the protein, even though typical intracellular findings in granulocytes could not be detected.

Funding

• Government Support – Non-U.S.