MYH9 Variant p.(Arg424Gly) Alters Nonmuscle Myosin IIA Contraction, Causing Atypical MYH9-related Disease

TL;DR

A new MYH9 gene variant causes a rare disease by increasing the activity of a muscle-related protein, leading to kidney and liver issues.

Contribution

This study identifies a novel gain-of-function MYH9 variant causing atypical MYH9-related disease.

Findings

The p.(Arg424Gly) variant increases ATP turnover and motor activity of nonmuscle myosin IIA.

The variant is fully segregating in a family and causes proteinuric kidney disease and elevated liver enzymes.

The disease mechanism is linked to enhanced intrinsic motor activity of the variant protein.

Abstract

Pathogenic variants in myosin heavy chain 9 (MYH9), encoding the heavy chain of nonmuscle myosin IIA (NMMIIA), cause autosomal-dominant MYH9-related disease that may include proteinuric kidney disease, macrothrombocytopenia, cataract, sensorineural deafness, and elevated liver enzymes.

Whole exome sequencing and segregation analysis were performed in a patient with end-stage renal disease. Histology of kidney and liver biopsies was assessed and blood smears were examined for the presence of Döhle-like bodies. Deformability cytometry and monocyte migration assays were performed. Immortalized podocytes and primary skin fibroblasts of 1 patient were transfected with plasmids containing MYH9 wild type (WT) or the p.(Arg424Gly) variant. Biochemical studies using recombinantly produced proteins were conducted to assess the variant’s impact on adenosine triphosphate (ATP) turnover and motor function.

We identified the likely pathogenic heterozygous MYH9 variant c.1270C>G, p.(Arg424Gly) in all affected members of a nonconsanguineous family. Typical microscopic findings, such as Döhle-like bodies or NMMIIA conglomerates were absent. Nonetheless, all patients presented with proteinuric kidney disease, elevated liver enzymes, and intermittent thrombocytopenia. The altered protein showed increased ATP turnover in the presence of actin and enhanced motor activity under both unloaded and loaded conditions.

We identified a novel fully segregating MYH9 variant causing MYH9-related disease. Based on biochemical findings, we report the first gain-of-function variant of MYH9. We propose that the enhanced intrinsic motor activity of the p.(Arg424Gly) variant is a key contributor to the disease mechanism. Incorporation of the p.(Arg424Gly) variant into nonmuscle myosin IIA filaments and higher-order actomyosin assemblies may, in principle, affect actomyosin dynamics.

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