Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease

Verver, Eva J J; Topsakal, Vedat; Kunst, Henricus P. M.; Huygen, P.L.M.; Heller, Paula G.; Pujol-Moix, Núria; Savoia, Anna; Benazzo, Marco; Fierro, Tiziana; Grolman, Wilko; Gresele, Paolo; Pecci, Alessandro

doi:10.1097/aud.0000000000000198

Cited by 24 publications

(20 citation statements)

References 30 publications

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“…The important functions of NM IIA are reflected in the embryonic lethality of knockout mice and demonstrated by its mutation-related diseases. Mutations in the MYH9 gene encoding NMHC IIA cause an autosomal-dominant disorder, namely MYH9-RD which has a complex phenotype characterized by macrothrombocytopenia with giant platelets and leukocyte inclusion bodies and syndromic forms combining these hematological features with deafness and/or nephropathy and/or cataracts [ 45 , 47 – 48 ]. At present, 49 MYH9 mutations have been reported to be associated with MYH9-RD [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of MYH9 locus for high efficient gene knock-in and stable expression in mouse embryonic stem cells

Liu

Guo³

et al. 2018

PLoS ONE

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Targeted integration of exogenous genes into so-called safe harbors/friend sites, offers the advantages of expressing normal levels of target genes and preventing potentially adverse effects on endogenous genes. However, the ideal genomic loci for this purpose remain limited. Additionally, due to the inherent and unresolved issues with the current genome editing tools, traditional embryonic stem (ES) cell-based targeted transgenesis technology is still preferred in practical applications. Here, we report that a high and repeatable homologous recombination (HR) frequency (>95%) is achieved when an approximate 6kb DNA sequence flanking the MYH9 gene exon 2 site is used to create the homology arms for the knockout/knock-in of diverse nonmuscle myosin II (NM II) isoforms in mouse ES cells. The easily obtained ES clones greatly facilitated the generation of multiple NM II genetic replacement mouse models, as characterized previously. Further investigation demonstrated that though the targeted integration site for exogenous genes is shifted to MYH9 intron 2 (about 500bp downstream exon 2), the high HR efficiency and the endogenous MYH9 gene integrity are not only preserved, but the expected expression of the inserted gene(s) is observed in a pre-designed set of experiments conducted in mouse ES cells. Importantly, we confirmed that the expression and normal function of the endogenous MYH9 gene is not affected by the insertion of the exogenous gene in these cases. Therefore, these findings suggest that like the commonly used ROSA26 site, the MYH9 gene locus may be considered a new safe harbor for high-efficiency targeted transgenesis and for biomedical applications.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of MYH9 locus for high efficient gene knock-in and stable expression in mouse embryonic stem cells

Liu

Guo³

et al. 2018

PLoS ONE

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“…MYH9‐related disease patients can present with Epstein syndrome, Fechtner syndrome and macrothrombocytopenia where variants in different protein domains can result in these phenotypes associated with individual health concerns . The identified c.287C > T; p.(Ser96Leu) variant in patient 189 is within the interface between the SH3‐like motif and the motor domain of the Head protein domain (SH3/MD I protein region) of the MYH9 protein, and variants in this region have been associated with a high risk of later onset hearing loss and a lower risk for nephropathy . The sister and father of patient 189 were found be heterozygous for the mutation, so this may prompt additional health concerns for them as well, highlighting the potential impact of a pediatric genetic diagnosis on other family members.…”

Section: Discussionmentioning

confidence: 99%

Utility and limitations of exome sequencing in the molecular diagnosis of pediatric inherited platelet disorders

et al. 2017

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Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology. We studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to: (1) examine the performance of the exome test for IPD genes, (2) determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, (3) to evaluate the frequency of variants of uncertain significance identified, and (4) to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis. We established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. In conclusion, ES has the potential to molecularly diagnose causes of IPD, and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned.

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“…Despite the genetic correlation, the exact mechanisms, particularly for hearing loss, remain unclear. 39,42,43 Up to 35% of MYH9-related disorder affected individuals have no family history. 40 As the bleeding tendency is mild, cases may not be identified until adulthood.…”

Section: Platelet Disordersmentioning

confidence: 99%

Genetic and Molecular Testing in Thrombosis and Hemostasis: Informing Surveillance, Treatment, and Prognosis

Crispin

Koo

2019

Semin Thromb Hemost

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The understanding of molecular mechanisms brought about by the rapid expansion of gene sequencing has helped to characterize molecular interactions underpinning normal hemostasis and identify inherited and acquired risks for thrombosis and hemorrhage. The widespread availability of molecular testing may serve to replace some currently available investigations with more precise diagnostic tools and add to phenotypic tests. Molecular studies will increasingly enable prenatal diagnosis, confirm difficult diagnostic challenges, early intervention, and assist in prognostication. This approach facilitates specific individualization of treatment options, with personally targeted therapy expected to increase. There remain many challenges, however, in the clinic. Prior to any test there should be consideration of how the results may influence treatment, and also how they may affect the patient within their familial and social environments. Massive parallel sequencing has the capacity to produce results that create uncertainty that needs to be considered prior to testing. In this context, the potential benefits of adding phenotypic and genotypic personal data to large databases should be discussed with patients. There is a paradox in that personalized medicine is dependent on large datasets to interpret the significance of genetic variation. This review will provide an outline of specific current and emerging roles for molecular testing for the personalization of care in the practice of thrombosis and hemostasis and highlight principles that can be implemented as new opportunities inevitably arise with the rapid expansion of knowledge from genomics.

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Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease

Cited by 24 publications

References 30 publications

Identification and characterization of MYH9 locus for high efficient gene knock-in and stable expression in mouse embryonic stem cells

Identification and characterization of MYH9 locus for high efficient gene knock-in and stable expression in mouse embryonic stem cells

Utility and limitations of exome sequencing in the molecular diagnosis of pediatric inherited platelet disorders

Genetic and Molecular Testing in Thrombosis and Hemostasis: Informing Surveillance, Treatment, and Prognosis

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