Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations
Rattachement africain : it. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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 six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in platelets and granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulating progenitors. NMMHC-IIA distribution in Mks 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 Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of platelets and 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 greater than that measured in platelets and Mks, 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, whereas 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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations
- Date Crossref
- 14/09/2005
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Pavia Department of Internal Medicine pays non établi dans la noticeUniversité ou école supérieure
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Policlinico San Matteo Fondazione pays non établi dans la noticeÉtablissement de santé
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Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
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IRCCS Materno Infantile Burlo Garofolo pays non établi dans la noticeÉtablissement de santé
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San Matteo Policlinic pays non établi dans la noticeÉtablissement de santé
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IRCCS Fondazione Policlinico San Matteo pays non établi dans la noticeÉtablissement de santé
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IRCCS pediatrico Burlo Garofolo pays non établi dans la noticeInstitution
Department of Internal Medicine — University of Pavia, Policlinico San Matteo Fondazione et Istituti di Ricovero e Cura a Carattere Scientifico, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.