title: Identification of three in-frame deletion mutations in MYH9 disorders suggesting an important hot spot for small rearrangements in MYH9 exon 24.
abstract: MYH9 disorders include hereditary macrothrombocytopenias with leukocyte inclusion bodies. Among more than 200 genetically confirmed families, the vast majority of cases exhibit single point mutations including substitutions and deletions of the COOH-terminus in the protein-coding sequence of MYH9. Only four in-frame deletions have been reported to date. In the current study, we describe three in-frame deletions including p.E1084del, p.E1066_A1072del and p.G1055_Q1068del, all of which are localized to exon 24. Interestingly, these three deletions were found to induce the diverse clinical manifestations on the non-hematological symptoms, while they equally demonstrated type I staining of inclusion bodies. As a result of these findings, we suggest that exon 24 represents a potential 'hot spot' for unequal homologous recombination, which may generate in-frame deletions in the coiled-coil rod of non-muscle myosin heavy chain-IIA. The exact length and position of these deletions may also determine the severity of the non-hematological manifestations, however does not appear to affect the morphology of the leukocyte inclusion bodies. These findings further our current understanding of the molecular pathogenesis underlying MYH9 disorders.
authors.affiliation: Department of Hematology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, 228-8555 Kanagawa, Japan. miyazakk@med.kitasato-u.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujii
authors.forename: Masaaki
authors.initials: M
authors.lastname: Higashihara
mesh_terms: D000328:Adult; D003062:Codon; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D011995:Recombination, Genetic; D017384:Sequence Deletion; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: D003062:Codon; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains