Moyamoya-like cerebrovascular disease in a child with a novel mutation in myosin heavy chain 11.
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ABSTRACT:
SUBMITTER: Keylock A
PROVIDER: S-EPMC5772163 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Moyamoya-like cerebrovascular disease in a child with a novel mutation in myosin heavy chain 11.
Keylock Annette A Hong Ying Y Saunders Dawn D Omoyinmi Ebun E Mulhern Ciara C Roebuck Derek D Brogan Paul P Ganesan Vijeya V Eleftheriou Despina D
Neurology 20171220 3
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Project description:BackgroundHeavy chain phosphorylation plays a central role in regulating myosin II bipolar filament assembly in Dictyostelium, as well as in higher eukaryotic nonmuscle cells. Our previous work has demonstrated that the WD-repeat domain of Dictyostelium myosin II heavy chain kinase B (MHCK-B), unlike its counterpart in MHCK-A, is not absolutely required for targeting of the kinase to phosphorylate MHC. Thus, we tested the hypothesis that an asparagine-rich and structurally disordered region that is unique to MHCK-B can by itself function in substrate targeting.FindingsBiochemical assays comparing the activities of full-length MHCK-B, a truncation lacking only the WD-repeat domain (B-Delta-WD), and a truncation lacking both the N-rich region and the WD-repeat domain (B-Delta-N-WD) revealed that the N-rich region targets MHCK-B to phosphorylate MHC in a manner that leads to bipolar filament disassembly. This targeting is physiologically relevant since cellular over-expression of the B-Delta-WD truncation, but not the B-Delta-N-WD truncation, leads to dramatically reduced levels of myosin II filament assembly and associated defects in cytokinesis and multicellular development.ConclusionsThe results presented here demonstrate that an intrinsically unstructured, and asparagine-rich, region of a MHCK-B can mediate specific targeting of the kinase to phosphorylate myosin II heavy chain. This targeting involves a direct binding interaction with myosin II filaments. In terms of regulating myosin bipolar filament assembly, our results suggest that factors affecting the activity of this unique region of MHCK-B could allow for regulation of MHCK-B in a manner that is distinct from the other MHCKs in Dictyostelium.
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Project description:We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy. The disorder has previously been described in a family with an "autosomal dominant myopathy, with joint contractures, ophthalmoplegia, and rimmed vacuoles." Linkage analysis and radiation hybrid mapping showed that the gene locus (Human Genome Map locus name: IBM3) is situated in a 2-Mb region of chromosome 17p13, where also a cluster of MyHC genes is located. These include the genes encoding embryonic, IIa, IIx/d, IIb, perinatal, and extraocular MyHCs. Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal. This observation prompted us to investigate the MyHC-IIa gene, since MyHC-IIa is the major isoform in type 2A fibers. The complete genomic sequence for this gene was deduced by using an "in silico" strategy. The gene, found to consist of 38 exons, was subjected to a complete mutation scan in patients and controls. We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region. By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family.
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Project description:This study aimed to determine whether measurements of cerebrovascular reserve and oxygenation, assessed with spin relaxation rate R2', yield similar information about pathology in pre-operative Moyamoya disease patients, and to assess whether R2' is a better measure of oxygenation than other proposed markers, such as R2* and R2. Twenty-five pre-operative Moyamoya disease patients were scanned at 3.0T with acetazolamide challenge. Cerebral blood flow mapping with multi-delay arterial spin labeling, and R2*, R2, and R2' mapping with Gradient-Echo Sampling of Free Induction Decay and Echo were performed. No baseline cerebral blood flow difference was found between angiographically abnormal and normal regions (49 ± 12 vs. 48 ± 11 mL/100 g/min, p = 0.44). However, baseline R2' differed between these regions (3.2 ± 0.7 vs. 2.9 ± 0.6 s-1, p < 0.001), indicating reduced oxygenation in abnormal regions. Cerebrovascular reserve was lower in angiographically abnormal regions (21 ± 38 vs. 41 ± 26%, p = 0.001). All regions showed trend toward significantly improved oxygenation post-acetazolamide. Regions with poorer cerebrovascular reserve had lower baseline oxygenation (Kendall's τ = -0.24, p = 0.003). A number of angiographically abnormal regions demonstrated preserved cerebrovascular reserve, likely due to the presence of collaterals. Finally, of the concurrently measured relaxation rates, R2' was superior for oxygenation assessment.
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Project description:Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding ?-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n?=?125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease.
| S-EPMC3229838 | biostudies-literature
Project description:We have cloned a full-length cDNA encoding a novel myosin II heavy chain kinase (mhckC) from Dictyostelium. Like other members of the myosin heavy chain kinase family, the mhckC gene product, MHCK C, has a kinase domain in its N-terminal half and six WD repeats in the C-terminal half. GFP-MHCK C fusion protein localized to the cortex of interphase cells, to the cleavage furrow of mitotic cells, and to the posterior of migrating cells. These distributions of GFP-MHCK C always corresponded with that of myosin II filaments and were not observed in myosin II-null cells, where GFP-MHCK C was diffusely distributed in the cytoplasm. Thus, localization of MHCK C seems to be myosin II-dependent. Cells lacking the mhckC gene exhibited excessive aggregation of myosin II filaments in the cleavage furrows and in the posteriors of the daughter cells once cleavage was complete. The cleavage process of these cells took longer than that of wild-type cells. Taken together, these findings suggest MHCK C drives the disassembly of myosin II filaments for efficient cytokinesis and recycling of myosin II that occurs during cytokinesis.
| S-EPMC138637 | biostudies-literature
Project description:Masticatory myosin is widely expressed among several vertebrate classes. Generally, the expression of masticatory myosin has been associated with high bite force for a carnivorous feeding style (including capturing/restraining live prey), breaking down tough plant material and defensive biting in different species. Masticatory myosin expression in the largest mammalian order, Rodentia, has not been reported. Several members of Rodentia consume large numbers of tree nuts that are encased in very hard shells, presumably requiring large forces to access the nutmeat. We, therefore, tested whether some rodent species express masticatory myosin in jaw-closing muscles. Myosin isoform expression in six Sciuridae species was examined, using protein gel electrophoresis, immunoblotting, mass spectrometry and RNA analysis. The results indicate that masticatory myosin is expressed in some Sciuridae species but not in other closely related species with similar diets but having different nut-opening strategies. We also discovered that the myosin light chain 1 isoform associated with masticatory myosin heavy chain, in the same four Sciuridae species, is the embryonic/atrial isoform. We conclude that rodent speciation did not completely eliminate masticatory myosin and that its persistent expression in some rodent species might be related to not only diet but also to feeding style.
| S-EPMC6518301 | biostudies-literature
Project description:Protein arginylation is a posttranslational modification with an emerging global role in the regulation of actin cytoskeleton. To test the role of arginylation in the skeletal muscle, we generated a mouse model with Ate1 deletion driven by the skeletal muscle-specific creatine kinase (Ckmm) promoter. Ckmm-Ate1 mice were viable and outwardly normal; however, their skeletal muscle strength was significantly reduced in comparison to controls. Mass spectrometry of isolated skeletal myofibrils showed a limited set of proteins, including myosin heavy chain, arginylated on specific sites. Atomic force microscopy measurements of contractile strength in individual myofibrils and isolated myosin filaments from these mice showed a significant reduction of contractile forces, which, in the case of myosin filaments, could be fully rescued by rearginylation with purified Ate1. Our results demonstrate that arginylation regulates force production in muscle and exerts a direct effect on muscle strength through arginylation of myosin.
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Project description:For moyamoya disease (MMD) patients who suffered an acute ischemic attack, the infarction patterns on DWI and its association with recurrent adverse cerebrovascular events (ACEs) after bypass surgery remain unknown. 327 patients who suffered an acute ischemic attack and received following revascularization surgery were retrospectively reviewed and were divided into three patterns according to the lesion number and distribution on DWI that obtained within 7 days of onset: no acute infarction (NAI), single acute infarction (SAI), and multiple acute infarctions (MAIs). We used Cox proportional hazard models to estimate hazard ratios (HR) for associations of infarction patterns and the risk of recurrent ACEs and strokes. Over a median follow-up of 41 months (IQR 26-60), there were 61 ACEs and 27 strokes. Compared to the NAI cohort, patients with SAI (HR, 2.92; 95% CI, 1.41-6.05; p = 0.004) and MAIs (HR, 4.44; 95% CI, 2.10-9.41; p < 0.001) were associated with higher risk of ACEs recurrences. In analysis adjusted for age and surgery modalities, the corresponding HR was 2.90 (95% CI: 1.41-5.98) for SAI and 4.10 (95% CI: 1.95-8.63) for MAIs, and this effect remained persistent on further adjustment for several potential confounders. Similar but less precise association was found in separate analysis that only takes into account stroke recurrences. Thus, different infarction patterns on DWI imply different risks of recurrent ACEs, and more attention should be paid to prevent ACEs in MMD patients with MAIs.
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Project description:We developed a 5'RNA-seq methodology to concurrently assess gene expression and start-site usage changes. We applied this methodology to study hypertrophic cardiomyopathy in mice harboring a human deleterious mutation.
2013-11-05 | GSE52038 | GEO
Project description:Myosinopathies are defined as a group of muscle disorders characterized by mutations in genes encoding myosin heavy chains. Their exact molecular and cellular mechanisms remain unclear. In the present study, we have focused our attention on a MYH1-related E321G amino acid substitution within the head region of the type IIx skeletal myosin heavy chain, associated with clinical signs of atrophy, inflammation and/or profound rhabdomyolysis, known as equine myosin heavy chain myopathy. We performed Mant-ATP chase experiments together with force measurements on isolated IIx myofibres from control horses (MYH1E321G-/-) and Quarter Horses homozygous (MYH1E321G+/+) or heterozygous (MYH1E321G+/-) for the E321G mutation. The single residue replacement did not affect the relaxed conformations of myosin molecules. Nevertheless, it significantly increased its active behaviour as proven by the higher maximal force production and Ca2+ sensitivity for MYH1E321G+/+ in comparison with MYH1E321G+/- and MYH1E321G-/- horses. Altogether, these findings indicate that, in the presence of the E321G mutation, a molecular and cellular hyper-contractile phenotype occurs which could contribute to the development of the myosin heavy chain myopathy.
| S-EPMC8699922 | biostudies-literature