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

AbstractIntroduction Pathogenic variants in MYH9, encoding the heavy chain of non-muscle myosin IIA, cause autosomal-dominant MYH9-related disease that may include proteinuric kidney disease, macrothrombocytopenia, cataract, sensorineural deafness and elevated liver enzymes. Methods 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 one patient were transfected with plasmids containing MYH9 WT or the p.(Arg424Gly) variant. Biochemical studies using recombinantly produced proteins were conducted to assess the variant's impact on ATP turnover and motor function. Results We identified the likely pathogenic heterozygous MYH9 variant c.1270C>G, p.(Arg424Gly) in all affected members of a non-consanguineous family. Typical microscopic findings such as Döhle-like bodies or non-muscle myosin IIA 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. Conclusions 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 non-muscle myosin IIA filaments and higher-order actomyosin assemblies may, in principle, affect actomyosin dynamics.