1. MYH9‐related disease mutations cause abnormal red blood cell morphology through increased myosin‐actin binding at the membrane
- Author
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Roberta B. Nowak, Rémi Favier, Lydie Da Costa, Alyson S. Smith, Anastasiya Demenko, Velia M. Fowler, Kasturi Pal, Carlo Zaninetti, and Alessandro Pecci
- Subjects
Male ,Hearing Loss, Sensorineural ,Erythrocytes, Abnormal ,medicine.disease_cause ,Article ,Motor protein ,03 medical and health sciences ,0302 clinical medicine ,Myosin ,medicine ,Humans ,Gene ,Actin ,Mutation ,Myosin Heavy Chains ,medicine.diagnostic_test ,Chemistry ,Erythrocyte Membrane ,Complete blood count ,Hematology ,Thrombocytopenia ,Phenotype ,Actins ,Cell biology ,Red blood cell ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,030215 immunology - Abstract
MYH9-related disease (MYH9-RD) is a rare, autosomal dominant disorder caused by mutations in MYH9, the gene encoding the actin-activated motor protein non-muscle myosin IIA (NMIIA). MYH9-RD patients suffer from bleeding syndromes, progressive kidney disease, deafness, and/or cataracts, but the impact of MYH9 mutations on other NMIIA-expressing tissues remains unknown. In human red blood cells (RBCs), NMIIA assembles into bipolar filaments and binds to actin filaments (F-actin) in the spectrin-F-actin membrane skeleton to control RBC biconcave disk shape and deformability. Here, we tested the effects of MYH9 mutations in different NMIIA domains (motor, coiled-coil rod, or non-helical tail) on RBC NMIIA function. We found that MYH9-RD does not cause clinically significant anemia and that patient RBCs have normal osmotic deformability as well as normal membrane skeleton composition and micron-scale distribution. However, analysis of complete blood count data and peripheral blood smears revealed reduced hemoglobin content and elongated shapes, respectively, of MYH9-RD RBCs. Patients with mutations in the NMIIA motor domain had the highest numbers of elongated RBCs. Patients with mutations in the motor domain also had elevated association of NMIIA with F-actin at the RBC membrane. Our findings support a central role for motor domain activity in NMIIA regulation of RBC shape and define a new sub-clinical phenotype of MYH9-RD.
- Published
- 2019