title: Advances in the understanding of MYH9 disorders.
abstract: OBJECTIVE
  MYH9 disorders are autosomal dominant macrothrombocytopenias with leukocyte inclusion bodies caused by mutations in MYH9, the gene for the nonmuscle myosin heavy chain IIA. May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes belong to MYH9 disorders. The present review summarizes the recent advances in genetic diagnosis and our understanding of the pathogenetic mechanisms of MYH9 mutations and the development of nonhematological complications.
  
  
  RESULTS
  A genotype-phenotype cohort study showed that patients with an MYH9 mutation in the motor head domain of myosin IIA have severe macrothrombocytopenia and are at a high risk for the development of glomerulonephritis and deafness. Among these, Arg702 mutations are associated with the most severe phenotype. In-vitro studies on cultured megakaryocytes elucidated that myosin IIA inhibits proplatelet formation. The loss of myosin IIA function owing to MYH9 mutations promotes proplatelet formation and may trigger precocious and premature platelet release, resulting in macrothrombocytopenia. Giant platelets only residually express mutant myosin IIA that has a loss of function and cannot participate in the reorganization of cytoskeletal contractile structures. Renal histopathological and immunochemical studies have suggested that glomerulonephritis in MYH9 disorders is caused by podocyte malfunction owing to defects in the myosin IIA structure and MYH9 expression.
  
  
  CONCLUSIONS
  MYH9 disorders are not merely benign hematological abnormalities, but serious syndromic disorders affecting the kidney, inner ear, and lens. A genetic diagnosis is mandatory for an accurate prognosis of nonhematological complications and management or possibly prophylactic treatment.
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. kunishis@nnh.hosp.go.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Saito
mesh_terms: D025063:Chromosome Disorders; D003638:Deafness / Q000235:genetics; D005921:Glomerulonephritis / Q000235:genetics*; D006801:Humans; D020409:Molecular Motor Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000502:physiology; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics* / Q000503:physiopathology; D034061:Thrombopoiesis
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains