MYH9-related disease mutations cause abnormal red blood cell morphology through increased myosin-actin binding at the membrane.

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.

• Authors: Alyson S Smith, Kasturi Pal, Roberta B Nowak, Anastasiya Demenko, Carlo Zaninetti, Lydie Da Costa, Remi Favier, Alessandro Pecci, Velia M Fowler
• Journal: American journal of hematology (Am J Hematol) Vol. 94 Issue 6 Pg. 667-677 (06 2019) ISSN: 1096-8652 [Electronic] United States
• PMID: 30916803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Actins
• MYH9 protein, human
• Myosin Heavy Chains

Topics

• Actins (genetics, metabolism)
• Erythrocyte Membrane (genetics, metabolism, pathology)
• Erythrocytes, Abnormal (metabolism, pathology)
• Female
• Hearing Loss, Sensorineural (genetics, metabolism, pathology)
• Humans
• Male
• Mutation
• Myosin Heavy Chains (genetics, metabolism)
• Thrombocytopenia (congenital, genetics, metabolism, pathology)