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Human Molecular Genetics Advance Access published online on September 14, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi344
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 12, 2005
Accepted September 9, 2005

Article

Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations

Alessandro Pecci 1*, Ilaria Canobbio 2, Alessandra Balduini 2, Lucia Stefanini 2, Barbara Cisterna 1, Carmela Marseglia 3, Patrizia Noris 1, Anna Savoia 4, Carlo L. Balduini 1, and Mauro Torti 2

1 Department of Internal Medicine, IRCCS Policlinico San Matteo, University of Pavia, piazzale Golgi, 27100 Pavia, Italy
2 Centre of Excellence for Applied Biology, University of Pavia, via Bassi, 27100 Pavia, Italy
3 Division of Hematology, IRCCS Policlinico San Matteo, piazzale Golgi, 27100 Pavia, Italy
4 Telethon Institute of Genetics and Medicine (TIGEM), via Castellino, 80131 Napoli, Italy

* To whom correspondence should be addressed.
Alessandro Pecci, E-mail: alessandro.pecci{at}unipv.it


  Abstract

Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinical phenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associated with deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects are either completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiency or a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated 11 patients from 6 pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in platelets and granulocytes isolated from peripheral blood, and in megakaryocytes cultured from circulating progenitors. NMMHC-IIA distribution in megakaryocytes and granulocytes was also assessed. We demonstrated that all the investigated patients had a 50% reduction of NMMHC-IIA expression in platelets, and that a similar defect was present also in megakaryocytes. In subjects with R1933X and E1945X mutations the whole NMMHC-IIA of platelets and megakaryocytes was wild-type. No NMMHC-IIA inclusions were observed at any time of megakaryocyte maturation. In granulocytes the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and megakaryocytes, and we found that wild-type protein was sequestered within most of the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, while in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies. The finding that the same mutations act through different mechanisms in different cells is surprising and requires further investigation.


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