Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinicalphenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associatedwith deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects areeither completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiencyor a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated11 patients from six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in plateletsand granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulatingprogenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that allthe investigated patients had a 50% reduction of NMMHC-IIA expression in platelets and that a similar defectwas present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of plateletsand Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulocytes,the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greaterthan that measured in platelets and Mks, and we found that wild-type protein was sequestered within mostof the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA inmegakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations,whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusionbodies. The finding that the same mutations act through different mechanisms in different cells is surprisingand requires further investigation.

Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.

Cisterna B.;Savoia A.;
2005

Abstract

Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinicalphenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associatedwith deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects areeither completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiencyor a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated11 patients from six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in plateletsand granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulatingprogenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that allthe investigated patients had a 50% reduction of NMMHC-IIA expression in platelets and that a similar defectwas present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of plateletsand Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulocytes,the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greaterthan that measured in platelets and Mks, and we found that wild-type protein was sequestered within mostof the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA inmegakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations,whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusionbodies. The finding that the same mutations act through different mechanisms in different cells is surprisingand requires further investigation.
MYH9 mutations
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/783781
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