Mutation spectrum and genotype‐phenotype correlations in a large French cohort of <scp>MYH</scp>9‐Related Disorders

Saposnik, Béatrice; Binard, Sylvie; Fenneteau, Odile; Nurden, Alan T.; Hurtaud‐Roux, Marie‐Françoise; Schlegel, Nicole

doi:10.1002/mgg3.68

Cited by 82 publications

(75 citation statements)

References 39 publications

(59 reference statements)

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“…However, recent investigations showed that this mutation is associated with not only sensorineural hearing loss but also macrothrombocytopenia and neutrophil inclusions. [8,9].…”

Section: Discussionmentioning

confidence: 99%

Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder

Wasano

Matsunaga

Ogawa

et al. 2016

Eur Arch Otorhinolaryngol

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MYH9 disorder is a rare autosomal-dominant disorder. We previously reported that it is caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9 disorder causes congenital macrothrombocytopenia accompanied by progressive sensorineural hearing loss, nephropathy, and cataract. However, there are few reports that describe the audiological features of MYH9 disorder. The objective of this study was to characterize auditory and other phenotypes of patients with MYH9 disorder. We examined nine subjects from one Japanese family. Audiological, ophthalmological, hematological, and imaging examinations were used to assess clinical features. We carried out genetic analysis of the causative gene, MYH9. Five subjects exhibited macrothrombocytopenia and neutrophil cytoplasmic inclusion bodies. Immunofluorescence analysis of neutrophil NMMHC-IIA revealed abnormal type II localization. Two subjects had high-frequency dominant hearing loss, which was adult onset and progressive. Only one subject had cataract. MYH9 sequencing analysis of all thrombocytopenic subjects revealed a heterozygous c.4270G>A mutation in exon 30 (p.D1424N). We identified five patients with MYH9 disorder from the family. The hearing impairment associated with MYH9 disorder in this family was characterized as adult onset, progressive, and high-frequency dominant. Hematological manifestations of MYH9 disorder show complete penetrance, whereas extra-hematological manifestations show incomplete penetrance and variable expressivity in this family.

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“…However, recent investigations showed that this mutation is associated with not only sensorineural hearing loss but also macrothrombocytopenia and neutrophil inclusions. [8,9].…”

Section: Discussionmentioning

confidence: 99%

Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder

Wasano

Matsunaga

Ogawa

et al. 2016

Eur Arch Otorhinolaryngol

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“…Hearing loss was early onset and severe in the DIAPH1 R1213* cases but develops in only 35% of MYH9-RD cases, typically after 10 years of age. 10 Cataract and nephropathy are reported in 5% and 21% of MYH9-RD cases, respectively, 10 but were absent in the DIAPH1 R1213* cases. Interestingly, mild neutropenia was frequently observed in the DIAPH1 R1213* cases (Table 1).…”

Section: Org Frommentioning

confidence: 97%

“…It has been proposed that the platelet phenotype associated with some MYH9, 13,14 ACTN1, 7 and TUBB1 15 variants results from aberrant cytoskeletal rearrangements during proplatelet formation, leading to altered platelet production. Cytoskeletal dysfunction may also underlie phenotypes such as hearing loss, cataract, and glomerulopathy associated with some variants in MYH9, 10,16 and periventricular nodular heterotopia and otopalatodigital syndromes associated with some variants in FLNA. 8 Here, we extend the repertoire of MTP by reporting the discovery of a new dominant syndromic disorder of platelet formation.…”

Section: Introductionmentioning

confidence: 99%

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Stritt

Nurden

Turro

et al. 2016

Blood

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Key Points• A gain-of-function variant in DIAPH1 causes macrothrombocytopenia and hearing loss and extends the spectrum of DIAPH1-related disease.• Our findings of altered megakaryopoiesis and platelet cytoskeletal regulation highlight a critical role for DIAPH1 in platelet formation.Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease andprovides new insight into the autoregulation of DIAPH1 activity.

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“…and sometimes hearing loss and cataract) [1,2]. The bleeding tendency is mild to moderate and easy bruising, epistaxis and menorrhagia are the most prevalent symptoms [3].…”

Section: Myh9-related Disorders (Myh9-mentioning

confidence: 99%

Thrombin generation in two families with MYH9-related platelet disorder

Zetterberg

Alle

Najm³

et al. 2015

Platelets

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MYH9-related platelet disorders are inherited macrothrombocytopenias with additional clinical manifestations including renal failure, hearing loss, pre senile cataract and inclusion bodies in leucocytes that are present in different combinations. The MYH9 gene codes for the cytoplasmic contractile protein non-muscular myosin heavy chain IIA, present in several tissues. The bleeding tendency is usually mild to moderate but rarely, thrombotic complications are also seen. We report on the thrombin generation potential (ETP) in patients with MYH9-related disease with and without arterial thrombosis.In family A, four affected members (c.5521G>A mutation causing p.(Glu1841Lys)) were evaluated. Three of them had a moderate bleeding tendency and in two renal insufficiency and hearing loss were already present. These two patients had an arterial thrombosis (myocardial infarction and pons infarction, respectively) before 50 years of age. In family B two members were affected (c.4679T>G, resulting in p.(Val1560Gly)). Their bleeding tendency was mild (bleeding scores 4 and 3, respectively). Thrombelastography (ROTEM) was normal in all six individuals. ETP was below the normal range in family B. However, in family A, the two members affected by thrombosis had a normal ETP, indicating that other factors compensated for the low platelet count and might have contributed to the arterial thrombosis.

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

Cited by 82 publications

References 39 publications

Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder

Late onset and high-frequency dominant hearing loss in a family with MYH9 disorder

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Thrombin generation in two families with MYH9-related platelet disorder

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