Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes

Seri, Marco; Cusano, Roberto; Gangarossa, Simone; Caridi, Gianluca; Bordo, Domenico; Nigro, Cristiana Lo; Ghiggeri, Gian Marco; Ravazzolo, Roberto; Savino, Maria; M, Del Vecchio; D’Apolito, Maria; Iolascon, Achille; Ll, Zelante; Savoia, Anna; Cl, Balduini; Noris, Patrizia; Magrini, Umberto; Belletti, Simona; Heath, Karen E.; Babcock, Melanie; Mj, Glucksman; Aliprandis, Elias; Bizzaro, Nicola; Rj, Desnick; Ja, Martignetti

doi:10.1038/79063

Cited by 379 publications

(56 citation statements)

References 26 publications

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“…Therefore, we suggest that the blood of any individual suspected of having MYH9-RD, even if inclusion bodies could not be detected with routine staining, should be examined with immunofluorescence staining. The NMMHC-IIA clusters in the inclusion bodies are unstable, so blood smears should be stained within 4 h of blood drawing [2,17]. …”

Section: Discussionmentioning

confidence: 99%

“…To date, only 44 different mutations of the MYH9 gene have been identified in 218 unrelated MYH9-RD families and most of them are missense mutations [15,16,17,18,19,20,21,22,23]. Missense mutations or small in-frame deletions affect either the motor head or the rod-tail domain, whereas the frameshift and nonsense alterations that lead to premature termination have been found only in the last exon [20].…”

Section: Introductionmentioning

confidence: 99%

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Clinical, Pathological, and Genetic Analysis of Ten Patients with MYH9-Related Disease

et al. 2012

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MYH9-related disease (MYH9-RD) is an autosomal dominant disorder caused by mutations in the MYH9 gene. It is characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like granulocyte inclusions. In this study we report 10 unrelated patients with MYH9-RD in whom the following seven MYH9 gene mutations were found: W33R, p.Q1443_K1445dup, R702H, D1424N, E1841K, R1933X, and E1945X (the first two were novel mutations). The region of the MYH9 mutation determines in some regards the phenotype, but clinical expression can vary between individuals with the same mutation. The neutrophil inclusion bodies of two patients were too small to be detected, but could be found with immunofluorescence staining. Immunoblotting analysis revealed that the calculated NMMHC-IIA/β-actin ratio for MYH9-RD neutrophils was 39% of normal controls. Kidney biopsy showed segmental glomerulosclerosis and NMMHC-IIA expression was decreased in podocytes. This disease is not as rare as originally thought. In any individual with persistent macrothrombocytopenia and no response to corticosteroids and immunosuppressive agents, even if neutrophil inclusions were inconspicuous in routine staining, MYH9-RD should be suspected.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical, Pathological, and Genetic Analysis of Ten Patients with MYH9-Related Disease

et al. 2012

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“…Since the discovery of the association of MYH9 with these disorders (Seri et al 2000; Heath et al 2001; Kunishima et al 2001), several series of patients have been reported (Dong et al 2005; Pecci et al 2008; Althaus and Greinacher 2009) as well as a number of isolated cases, in populations from different continents. A recent review reported at least 44 different MYH9 mutations in 218 MYH9-RD unrelated families (Balduini et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Mutation spectrum and genotype‐phenotype correlations in a large French cohort of MYH9‐Related Disorders

Saposnik

Binard

Fenneteau

et al. 2014

Molec Gen & Gen Med

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MYH9-Related Disorders are a group of rare autosomal dominant platelet disorders presenting as nonsyndromic forms characterized by macrothrombocytopenia with giant platelets and leukocyte inclusion bodies or as syndromic forms combining these hematological features with deafness and/or nephropathy and/or cataracts. They are caused by mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain II-A (NMMHC-IIA). Until now, at least 49 MYH9 mutations have been reported in isolated cases or small series but only rarely in large series. We report the results of an 8-year study of a large cohort of 109 patients from 37 sporadic cases and 39 unrelated families. We have identified 43 genetic variants, 21 of which are novel to our patients. A majority, 33 (76.7%), were missense mutations and six exons were preferentially targeted, as previously published. The other alterations were three deletions of one nucleotide, one larger deletion of 21 nucleotides, and one duplication. For the first time, a substitution T>A was found in the donor splice site of intron 40 (c.5765+2T>A). Seven patients, four from the same family, had two genetic variants. The analysis of the genotype-phenotype relationships enabled us to improve the knowledge of this heterogeneous but important rare disease.

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“…MYH9 -related disease ( MYH9 -RD) is an autosomal-dominant syndromic disorder deriving from mutations in MYH9 , the gene for the heavy chain of non-muscle myosin IIA (NMMHC-IIA) [1,2]. MYH9 -RD is characterized by a complex phenotype.…”

Section: Introductionmentioning

confidence: 99%

Cochlear implantation is safe and effective in patients with MYH9-related disease

Pecci

Verver

Schlegel

et al. 2014

Orphanet Journal of Rare Diseases

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BackgroundMYH9-related disease (MYH9-RD) is a rare syndromic disorder deriving from mutations in MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital thrombocytopenia and giant platelets and have a variable risk of developing sensorineural deafness, kidney damage, presenile cataract, and liver abnormalities. Almost all MYH9-RD patients develop the hearing defect, which, in many individuals, progresses to severe to profound deafness with high impact on quality of life. These patients are potential candidates for cochlear implantation (CI), however, no consistent data are available about the risk to benefit ratio of CI in MYH9-RD. The only reported patient who received CI experienced perisurgery complications that have been attributed to concurrent platelet defects and/or MYH9 protein dysfunction.MethodsBy international co-operative study, we report the clinical outcome of 10 patients with MYH9-RD and severe to profound deafness who received a CI at 8 institutions.ResultsNine patients benefited from CI: in particular, eight of them obtained excellent performances with restoration of a practically normal hearing function and verbal communication abilities. One patient had a slightly worse performance that could be explained by the very long duration of severe deafness before CI. Finally, one patient did not significantly benefit from CI. No adverse events attributable to MYH9-RD syndrome were observed, in particular no perisurgery bleeding complications due to the platelet defects were seen. Patients’ perioperative management is described and discussed.ConclusionsCI is safe and effective in most patients with MYH9-RD and severe to profound deafness and should be offered to these subjects, possibly as soon as they develop the criteria for candidacy.

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Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes

Cited by 379 publications

References 26 publications

Clinical, Pathological, and Genetic Analysis of Ten Patients with MYH9-Related Disease

Clinical, Pathological, and Genetic Analysis of Ten Patients with MYH9-Related Disease

Mutation spectrum and genotype‐phenotype correlations in a large French cohort of MYH9‐Related Disorders

Cochlear implantation is safe and effective in patients with MYH9-related disease

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