Each nemaline myopathy focused research publication listed here is a testament to the power of collaboration between AFBS and researchers who share our mission to drive progress toward treatments for nemaline myopathy. These scientific papers represent the cutting-edge discoveries and collaborations made possible through AFBS’s support, underlining our commitment to driving progress in nemaline myopathy research, ultimately striving for treatments and improved lives.
Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion
March 2025, Zachary Coulson, Justin Kolb, Nesrin Sabha, Esmat Karimi, Zaynab Hourani, Coen Ottenheijm, Henk Granzier and James J. Dowling
This research identified that a previous mouse model for the common Nemaline Myopathy-causing NEB gene deletion (ΔExon55) exhibited a much more severe condition than seen in human patients due to the unintended creation of a non-functional pseudoexon. To create a more accurate model, the researchers used CRISPR to remove this pseudoexon sequence. The resulting “hmz” mice showed significantly reduced pseudoexon formation and restored stable nebulin transcript expression, exhibiting characteristic features of human Nemaline Myopathy and surviving into later life, making them a valuable new tool for studying the disease and developing treatments.
An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Genedular and Reconfigurable Body Mounted Soft Robots
August 2024, Joshua S. Clayton, Mridul Johari, Rhonda L. Taylor, Lein Dofash, Georgina Allan, Gavin Monahan, Peter J. Houweling, Gianina Ravenscroft, and Nigel G. Laing
This study updates the catalog of ACTA1 gene variants, now totaling 607, with 447 classified as pathogenic or likely pathogenic, and links these variants to a growing number of disease phenotypes, primarily nemaline myopathy. Researchers propose refined guidelines for interpreting ACTA1 variants and discuss the challenges in establishing genotype-phenotype correlations, while also summarizing current animal models and preclinical treatments. This work provides valuable resources and recommendations for the study and interpretation of ACTA1 variants.
Future Directions for Respiratory Muscle Training in Neuromuscular Disorders: A Scoping Review
August 2024, Esmee S.B. van Kleef et al.
This scoping review examined 45 studies on respiratory muscle training (RMT) in neuromuscular disorders (NMDs), finding significant diversity in study designs and training protocols, which prevented definitive conclusions about RMT effectiveness. While patient adherence to RMT was high and no serious adverse events were reported, the variable effects on respiratory muscle strength and endurance highlight the need for further research. The review identifies key limitations and research gaps, offering recommendations for future studies to better understand the role of RMT in NMDs.
A Cross-sectional Study in 18 Patients with Typical and Mild Forms of Nemaline Myopathy in the Netherlands
August 2024, Esmee S.B. van Kleef et al.
This cross-sectional study characterized the clinical features of a Dutch Nemaline Myopathy (NM) patient cohort, assessing medical history, physical function, quality of life, and respiratory muscle function. Researchers found varying degrees of muscle weakness, with many patients requiring mobility aids or respiratory support, and identified common co-morbidities like spinal deformities. This characterization of the Dutch NM cohort provides valuable data for international collaboration and informs the design of future clinical trials.
Nemaline Myopathy Type 6 (NEM6) Caused by Variants in the KBTBD13 Gene
August 2024, Esmee S.B. van Kleef et al.
This cross-sectional study provides a detailed clinical characterization of 24 patients with Nemaline Myopathy type 6 (NEM6), the most prevalent type in the Netherlands, revealing a relatively mild clinical phenotype despite patient-reported functional difficulties, reduced quality of life, and increased fatigue and falls. Key symptoms included muscle weakness and slow movements, with functional testing showing mildly abnormal results, notably a markedly reduced muscle relaxation rate. This comprehensive overview of NEM6 clinical presentation and functional limitations distinguishes it from other forms of nemaline myopathy.
A Likely Pathogenic variant in the KBTBD13 Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6
August 2024, Esmee S.B. van Kleef et al.
This study characterized three patients with a novel c.1222C>A (p.Arg408Ser) variant in the KBTBD13 gene, confirming it as a likely pathogenic variant causing Nemaline Myopathy type 6 (NEM6).
Myosin ATPase Inhibition Fails to Rescue the Metabolically Dysregulated Proteome of Nebulin-deficient Muscle
August 2024, Jenni Laitila, Robert A. E. Seaborne, Natasha Ranu, Justin S. Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Edmar Zanoteli, Johanna Palmio, Sanna Huovinen, Henk Granzier, Julien Ochala
This study investigated the potential of Mavacamten, a drug that modulates muscle protein function, for treating Nemaline Myopathy (NM), a genetic muscle disease. While Mavacamten successfully corrected energy consumption issues in isolated muscle fibers from NM patients, short-term treatment in a mouse model did not significantly improve the muscle’s energy-related protein profile, suggesting that longer treatment durations or alternative approaches may be necessary.
Characterization of NEB Mutations in Patients Reveals Novel Nemaline Myopathy Disease Mechanisms and Omecamtiv Mecarbil Force Effects
April 2024, Esmat Karimi et al.
Some of the original and exciting findings include thin filament length being shorter or longer in these NEB patients, some patients had near-normal nebulin levels while others had significantly reduced levels, a positive correlation between nebulin levels and thin filament length was found, actin-binding sites were disrupted, and OM treatment substantially increased submax tension across all NEB cases.
Modular and Reconfigurable Body Mounted Soft Robots
April 2024, Tuo Liu, Taqi Abrar, and Jonathan Realmuto
This research introduces a novel design framework for soft wearable robots (exosuits) using textile-based, modular pneumatic actuators and 3D-printed end-caps for easy assembly. The modular architecture, combined with semi-rigid human-robot interfaces, allows for customizable exosuits adaptable to different joints, demonstrated effectively on a human leg mannequin, offering significant potential for assisting individuals with mobility impairments.
Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force
October 2023, Johan Lindqvist and Henk Granzier
This study investigated the effects of myostatin inhibition using the mRK35 antibody in a mouse model of nemaline myopathy, a common congenital myopathy characterized by muscle weakness and smallness. Treatment with mRK35 resulted in increased muscle mass and strength, suggesting that myostatin inhibition could be a potential therapeutic strategy for mitigating muscle deficits in this condition.
Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy
October 2023, Michael W Lawlor et al.
In a study using a mouse model of nemaline myopathy, researchers found that problems with energy metabolism and stress-related pathways play a role in the development of the condition. This insight may pave the way for new approaches to understand and potentially treat nemaline myopathy.
Different Mouse Models of Nemaline Myopathy Harboring ACTA1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology
October 2023, Michael W Lawlor et al.
Various mouse models of nemaline myopathy, which have specific genetic mutations, exhibit different issues related to how their cells use energy from mitochondria. This research sheds light on the complex nature of the disease and its connection to mitochondrial function in these models.
NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy
September 2023, Vandana A. Gupta et al.
This research shows that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. The findings suggest that Nrap is a disease modifier that affects skeletal muscle structure and function in NM; thus, therapeutic targeting of Nrap in nebulin-related NM and related diseases may be beneficial for patients.
Inspiratory Muscle Training in Nemaline Myopathy
September 2023, Jonne Doorduin et al.
This study explores the benefits of a breathing exercise program for individuals with nemaline myopathy, a rare muscle disorder. The research investigates how training the muscles used for breathing can improve respiratory function and overall well-being in these individuals
Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset
July 22, 2022
Vandana A Gupta et al.
This important study utilizes a model organism, zebrafish, to explore the roles of KLHL40, a component of the ubiquitin-proteasome system (UPS), in the development of skeletal muscle disease. The compelling data on proteome remodeling and UPS-regulation of biosynthetic secretion make this work interesting to biologists who study the UPS, muscle development and intracellular traffic.
NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy
December 2022, Julien Ochala et al.
Mutations in the NEB gene cause changes in muscle function and metabolism in nemaline myopathy by affecting a relaxed state of muscle fibers. This research sheds light on how these genetic changes impact muscle health.
Generation of two isogenic induced pluripotent stem cell lines from a 1-month-old nemaline myopathy patient harbouring a homozygous recessive c.121C > T (p.Arg39Ter) variant in the ACTA1 gene
August 2022, Joshua S. Clayton et al.
Scientists have successfully created two identical stem cell lines from a young patient with nemaline myopathy, who had a specific genetic mutation in the ACTA1 gene. This achievement paves the way for future research to better understand and potentially treat this rare muscle disorder.
Generation of an induced pluripotent stem cell line from a 3-month-old nemaline myopathy patient with a heterozygous dominant c.515C > A (p.Ala172Glu) variant in the ACTA1 gene
August 2022, Rhonda L. Taylor et al.
Researchers have successfully created a versatile stem cell line from a young patient with nemaline myopathy, who had a specific genetic mutation in the ACTA1 gene. This breakthrough opens doors to future investigations and potential therapies for this rare muscle disorder.
Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits.
August 2022, Henk Granzier et al.
Eliminating MuRF1, a protein, leads to increased muscle mass in nemaline myopathy models, but it doesn’t necessarily improve muscle function. This research suggests that while muscle size can be enhanced, other factors might be more critical for improving muscle performance in this condition.
Generation of two isogenic induced pluripotent stem cell lines from a 1-month-old nemaline myopathy patient harbouring a homozygous recessive
April 2022, Joshua S. Clayton et al.
This research explains the iPSC lines demonstrated typical morphology, expressed pluripotency markers, exhibited trilineage differentiation potential and displayed a normal karyotype. These isogenic lines represent a potential resource to investigate and model recessive ACTA1 disease in a human context.
NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy
2022, Julien Ochala et al.
The aim of the study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. The findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.
Recent advances in nemaline myopathy
July 2021, Jenni Laitila, Carina Wallgren-Pettersson
This research suggests a renewed clinical classification to replace the original one, summarizes what is known about the pathogenesis from mutations in each causative gene to the forms of nemaline myopathy described to date, and provides perspectives on pathogenetic mechanisms possibly open to therapeutic modalities.
A cross-sectional study of nemaline myopathy supplementary figures
January 2021, James J. Dowling, MD, PhD et al.
Fifty-seven individuals with NM were recruited at two family workshops, including 16 examined at both time points. Subjects were evaluated by clinical history and physical examination. In all, the group presented a comprehensive cross-sectional study of NM. The data identifies significant disabilities and supports a relatively stable disease course. They identified a need for further diagnostic investigation for the genetically unresolved group.
Triggering typical nemaline myopathy with compound heterozygousnebulin mutations reveals myofilament structural changes as pathomechanism
August 2020, Henk Granzier et al.
In this study, a mouse model was engineered to replicate typical nemaline myopathy (NM) with specific genetic mutations, resulting in stunted growth and muscle weakness. Examination of these mice revealed structural changes in muscle fibers, including twisted actin filaments, altered behavior of proteins like tropomyosin and troponin, and increased spacing between muscle fibers, shedding light on potential therapeutic targets for nebulin-based typical NM.
Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb
February 2020, Jenni M. Laitila et al.
No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. This research aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease.The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.
Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function
January 2020, Frank Li et al.
This research studied whether sarcomeric structure and function can be improved by introducing nebulin’s Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied.
Omecamtiv mecarbil lowers the contractile deficit in a mouse model of nebulin-based nemaline myopathy
November 2019, Henk Granzier et al.
For this research, a new medication called Omecamtiv mecarbil shows promise in improving muscle function in a specific mouse model of a rare muscle disorder. This research offers hope for potential treatments to enhance muscle strength in people with similar conditions.
Failure to identify modifiers of NEBULIN-related nemaline myopathy in two pre-clinical models of the disease
September 2019, James J. Dowling et al.
In two pre-clinical models, researchers couldn’t find factors that make NEBULIN-related nemaline myopathy better or worse.
Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy
April 2019, Vandana A Gupta et al.
In nemaline myopathy, there is a problem with how a protein called NRAP is broken down, and this contributes to the disease’s development. Researchers have found this dysregulation as a potential key factor in understanding the condition.
Myostatin Inhibition Using ActRIIB-mFc Does Not Produce Weight Gain or Strength in the Nebulin Conditional KO Mouse
December 2018, Michael W Lawlor, MD, PhD et al.
Using a substance called ActRIIB-mFc to block myostatin did not result in weight gain or increased strength in a specific mouse model, despite hopes for its potential benefits. This research highlights the need to explore alternative approaches for addressing muscle-related issues.
TNNT1 nemaline myopathy: natural history and therapeutic frontier
September 2018, Kevin A Strauss et al.
This study delves into the natural course of TNNT1 nemaline myopathy and explores new possibilities for potential treatments. It aims to better understand this condition and discover novel ways to improve the lives of affected individuals.