A5068373124- Cardiomyopathy and Myosin Studies
- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Cellular Mechanics and Interactions
- Genetic Neurodegenerative Diseases
- Cardiovascular Effects of Exercise
- Connective tissue disorders research
- Nuclear Structure and Function
- Ion channel regulation and function
- Transcranial Magnetic Stimulation Studies
- Microtubule and mitosis dynamics
- Trypanosoma species research and implications
Amsterdam UMC Location Vrije Universiteit Amsterdam
2013-2024
Amsterdam University Medical Centers
2019-2024
Vrije Universiteit Amsterdam
2023-2024
Amsterdam Neuroscience
2021
University Medical Center
2013-2018
University Hospital and Clinics
2013-2018
University of Arizona
2013-2015
Nemaline myopathy (NM) is a rare congenital characterised by hypotonia, muscle weakness, and often skeletal deformities with the presence of nemaline bodies (rods) in biopsy. The nebulin (NEB) gene most commonly mutated thought to account for approximately 50% genetically diagnosed cases NM. We undertook detailed morphological analysis 14 NEB-mutated NM patients different clinical forms define pathological patterns correlate them course genotype. Three groups were identified according...
Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and caused by mutations in genes encoding proteins that associated with skeletal muscle thin filament. Mechanisms underlying weakness poorly understood, but might involve length of filament, an important determinant force generation.We investigated sarcomere length-dependence force, a functional assay provides insights into contractile strength fibers as well filaments, from 51 patients myopathy...
Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations the gene encoding nebulin (NEB) are frequent cause of nemaline myopathy, most common non-dystrophic congenital mechanisms which NEB weakness remain largely unknown. To better understand these mechanisms, we have generated mouse model Neb exon 55 is deleted (NebΔExon55) to replicate founder mutation seen frequently patients with myopathy...
Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is frequently affected one. The codes for giant sarcomeric protein nebulin, plays a crucial role skeletal muscle contractile performance. Muscle weakness hallmark feature nemaline myopathy patients with mutations, and changes function, including lower calcium-sensitivity force generation. To date no therapy exists to treat myopathy. Here, we studied...
Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used multidisciplinary approach to investigate the mechanism of dysfunction 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is diagnostic hallmark TPM3-myopathy, and commonly accompanied skewing fibre-type ratios (either or fast fibre predominance). Patient contained normal three tropomyosin isoforms expression myosins troponins. Using...
The mechanisms that modulate the kinetics of muscle relaxation are critically important for function. A prime example impact impaired is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow relaxation, compromising contractility and daily life activities. role unknown, pathomechanism underlying undetermined. combination transcranial magnetic stimulation-induced fiber- sarcomere-contractility assays, low-angle x-ray diffraction,...
Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions ΔE218 ΔE224, resulting significant hypercontractile phenotype congenital stiffness, rather than weakness, respiratory failure one patient.The effect the on contractile properties dissected patient myofibers was measured. used quantitative vitro motility assay...
The effect of the fast skeletal muscle troponin activator, CK-2066260, on calcium-induced force development was studied in skinned fibers from wildtype (WT) and nebulin deficient (NEB KO) mice. Nebulin is a sarcomeric protein that when absent KO mouse) or present at low levels (nemaline myopathy (NM) patients with NEB mutations) causes weakness. We activation WT tested whether it might be therapeutic mechanism to increase strength muscle. measured tension-pCa relations without added...
Objective Nemaline myopathy (NM) is one of the most common congenital nondystrophic myopathies and characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause NM (ie, NEM3). encodes alpha‐actin 1, main constituent sarcomeric thin filament. The mechanisms which mutations contribute to weakness NEM3 incompletely understood. We hypothesized that dysfunction contributes patients. Methods To test this hypothesis, we performed contractility measurements individual...
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate contraction. Surprisingly, the gene encoding fast TnC (TNNC2) has not yet been implicated in disease. Here, we report 2 families with pathogenic variants TNNC2. Patients present distinct, dominantly inherited congenital Molecular dynamics simulations suggested that pathomechanisms by which cause disease include disruption binding sites for and troponin I. In line these findings, physiological...
Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is characterized by generalized skeletal muscle weakness, often from birth. To date, no therapy exists that enhances contractile strength of muscles NM patients. Mutations in NEB, encoding giant protein nebulin, are cause NM. The pathophysiology weakness patients with NEB mutations (NEB-NM) includes a lower calcium-sensitivity force generation. We propose generation NEB-NM offers therapeutic target. Levosimendan...
Abstract Nemaline myopathy, a disease of the actin-based thin filament, is one most frequent congenital myopathies. To date, no specific therapy available to treat muscle weakness in nemaline myopathy. We tested ability tirasemtiv, fast skeletal troponin activator that targets augment force—both vivo and vitro—in myopathy mouse model with mutation (H40Y) Acta1. In Acta1H40Y mice, treatment tirasemtiv increased force response muscles submaximal stimulation frequencies. This resulted reduced...
Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast ( TNNI2 ) TnI-slow TNNI1 ), are predominantly expressed in fast- slow-twitch myofibers, respectively. variants a rare cause of arthrogryposis, whereas have not been conclusively established to skeletal myopathy. We identified recessive loss-of-function as well dominant gain-of-function disease, each with distinct physiological consequences disease mechanisms. three families biallelic (F1:...
Abstract Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it clinical phenotype pathophysiological mechanisms. Rods were found 85% of biopsies light microscopy, 89% electron microscopy. A peculiar ring disposition rods resulting ring-rods fiber was observed. Cores 79% 83%...
KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although is expressed in cardiac muscle, involvement unknown. Here, we constructed pedigrees three families with p.R408C variant. In 65 evaluated patients, 12% presented left ventricle dilatation, 29% ventricular ejection fraction< 50%, 8% atrial fibrillation, 9% tachycardia, and 20% repolarization abnormalities. Five received an...
Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15–25% all nemaline myopathy cases. Patients harboring variants present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, severe cases, respiratory failure and death. To date, no specific treatments available. Since NEM3 is an actin-based thin filament disease, we tested ability tirasemtiv, fast skeletal troponin activator, to improve function...
Background: Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital is the most prevalent of nemaline in Netherlands and characterised by mild childhood-onset axial, proximal distal muscle weakness with prominent neck flexor combined slowness movements. The variant c.1222C > T p.(Arg408Cys) KBTBD13 gene, also called Dutch founder variant. Objective: To provide a comprehensive clinical functional characterisation three patients to assess pathogenicity newly identified gene. Results:...