Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy
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PROVIDER: PRJNA1321711 | ENA |
REPOSITORIES: ENA
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Project description:The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Submitted transcriptomic data represents gene expression profile of control and LAMA2-deficient human myogenic precursor cells derived from induced pluripotent stem cells which was analyzed to better understand the role of laminin-α2 in human cells.
2025-09-14 | GSE307443 | GEO
Project description:LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by LAMA2 mutations, leading to muscle degeneration, chronic inflammation, and fibrosis. Histopathological assessment of muscle biopsies from LAMA2-CMD patients and mouse models show clear evidence of inflammation, which oftentimes are regarded as one of the typical dystrophic hallmarks. However, the composition of immune cells in the laminin-deficient muscles remain understood. Consequently, targeted pharmacological intervention to reduce inflammation has never been tested. In this study, we characterized the immune landscape in dyW mouse model of LAMA2-CMD using RNA sequencing and flow cytometry. Transcriptomic analysis of dyW quadriceps identified 2,143 differentially expressed genes, with most of the upregulated genes belong to immune-related pathways. Lgals3 (Galectin-3) was significantly upregulated (log₂FC = 4.27, FDR p-value= 9.21x10-88) and identified as a key upstream regulator of the immune-related pathways. In parallel, flow cytometry analysis revealed elevated leukocyte (CD45⁺) infiltration, with macrophages as the predominant cell population. Pro-inflammatory (M1) macrophages were increased, whereas anti-inflammatory (M2) macrophages remained low, indicating persistent inflammation and impaired resolution. Interestingly, Galectin-3+ macrophages were significantly enriched, which strongly suggest that Galectin-3 drives inflammation in LAMA2-CMD. Treatment of dyW mice with TD-139, a Galectin-3 inhibitor, reduced leukocyte infiltration, decreased Galectin-3+ macrophages, and shifted macrophage polarization toward an M2 anti-inflammatory profile. In addition, RNA sequencing of TD-139-treated dyW muscles showed upregulation of muscle repair pathways and downregulation of fibrosis-related genes. These findings establish Galectin-3-expressing macrophages as an important player in LAMA2-CMD pathophysiology. Importantly, it warrants further investigation on the therapeutic potential of TD-139-mediated inhibition of Galectin-3, including long-term preclinical study, in LAMA2-CMD and potentially other dystrophic conditions driven by chronic immune activation.
2025-03-25 | GSE292894 | GEO
Project description:Laminin (merosin) deficient muscular dystrophy in dy/dy mouse diaphragm muscle, 8 weeks old Keywords: muscle, muscular dystrophy, laminin, merosin, diaphragm, mouse
2006-03-16 | GSE3252 | GEO
Project description:We report a a large deletion in the gene encoding for laminin subunit α2 (Lama2) in CHO pgsA745.
2016-11-20 | GSE75521 | GEO
Project description:Although recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not well-characterized. In this study, we applied next-generation sequencing-based copy number variation profiling in 114 individuals clinically diagnosed with laminin α2-related muscular dystrophy, including 96 who harboured LAMA2 mutations and 34 who harboured intragenic rearrangements. In total, we detected 18 distinct LAMA2 copy number variations that have been reported only among Chinese, 10 of which are novel. The frequency of CNVs in the cohort was 19.3%. Deletion of exon 4 was detected in 10 alleles of eight patients, accounting for 27% of all copy number variations. These patients are Han Chinese and were found to have the same haplotype and sequence at the breakpoint junction, suggesting that exon 4 deletion is a founder mutation in Chinese Han and a mutation hotspot. Moreover, the data highlight our approach, a modified next-generation sequencing assay, as a robust and sensitive tool to detect LAMA2 variants; the assay identifies 85.7% of breakpoint junctions directly alongside sequence information. The method can be applied to clinical samples to determine causal variants underlying various Mendelian disorders.
| S-EPMC6177444 | biostudies-literature
Project description:Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.
| S-EPMC7139799 | biostudies-literature
Project description:LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy and is triggered by mutations in LAMA2, coding for laminin α2 chain. Several phenotypes have been associated with LAMA2-CMD, including inflammation, fibrosis and increased oxidative stress. However, it is not yet known what mechanisms are faulty, right at disease onset, which in the mouse model of LAMA2-CMD dyW/dyW has been previously established to occur between embryonic days (E) 17.5 and E18.5. This transcriptomic analysis of fetal muscle fibers perfomed at E17.5 provides critical information regarding the genes and pathways that are altered in LAMA2-CMD right at the onset of the disease.
2024-09-23 | GSE253680 | GEO
Project description:Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin α2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin α2 chain.
| S-EPMC4701230 | biostudies-literature
Project description:BackgroundLaminin α2 deficient congenital muscular dystrophy, caused by mutations in the LAMA2 gene, is characterized by early muscle weakness associated with abnormal white matter signal on cerebral MRI.ObjectiveTo report on 4 patients with LAMA2 gene mutations whose original clinical features complicated the diagnosis strategy.MethodsClinical, electrophysiological, muscle imaging and histopathological data were retrospectively collected from all patients. DNA samples were analysed by next-generation sequencing or direct gene sequencing. Laminin α2 was analysed by western-blot and immunohistochemistry.ResultsThe four patients achieved independent walking. All had proximal muscle weakness with scapular winging and prominent joint contractures without peripheral neuropathy. During follow-up, two patients suffered from refractory epilepsy associated with brain leukoencephalopathy in one, polymicrogyria and lissencephaly without white matter changes in the other. In two patients, the distribution of fatty infiltration resembles that of collagen-VI related myopathies. Dilated cardiomyopathy contstartabstractwith conduction defects, suggestive of Emery-Dreifuss myopathy, emerged in two of them within the 4th decade. Molecular diagnosis remained elusive for many years. Finally, targeted capture-DNA sequencing unveiled the involvement of the LAMA2 gene in two families, and led us to further identify LAMA2 mutations in the remaining family using Sanger sequencing.ConclusionsThis report extends the clinical and radiological features of partial Laminin α2 deficiency since patients showed atypical manifestations including dilated cardiomyopathy with conduction defects in 2, epilepsy in 2, one of whom also had sole cortical brain abnormalities. Importantly, clinical findings and muscle imaging initially pointed to collagen-VI related disorders and Emery-Dreifuss muscular dystrophy.
| S-EPMC5240538 | biostudies-literature
Project description:Congenital muscular dystrophy type-1A (Lama2-CMD) and Duchenne Muscular dystrophy (DMD) result from deficiencies of laminin-α2 and dystrophin proteins, respectively. Although both proteins strengthen the sarcolemma, they are implicated in clinically distinct phenotypes. We used RNA-deep sequencing (RNA-Seq) of dy2J/dy2J, Lama2-CMD mouse model, skeletal muscle at 8 weeks of age to elucidate disease pathophysiology. This study is the first report of dy2J/dy2J model whole transcriptome profile. RNA-Seq of the mdx mouse model of DMD and WT mouse was carried as well in order to enable a novel comparison of dy2J/dy2J to mdx. A large group of shared differentially expressed genes (DEG) were found in dy2J/dy2J and mdx models (1,834 common DEG, (FDR) < 0.05). Enrichment pathway analysis using Ingenuity Pathway Analysis (IPA) showed enrichment of inflammation, fibrosis, cellular movement, migration and proliferation of cells, apoptosis and necrosis in both mouse models (p-values 3E-10 – 9E-37). Via Canonical pathway analysis; Actin cytoskeleton, Integrin, ILK, NF-kB, Renin-angiotensin, calcium signaling were also enriched and upregulated in both models (FDR<0.05). Interestingly, significant downregulation of Pax7 was detected in dy2J/dy2J compared to upregulation of this key regeneration gene in mdx mice. Pax3 and Mamstr genes were also downregulated in dy2J/dy2J compared to WT mice. These results may explain the distinct disease course and severity in these models. While the mdx model at that stage shows massive regeneration, the dy2J/dy2J shows progressive dystrophic process. Our data deepen our understanding of the molecular pathophysiology and suggest new targets for additional therapies to upregulate regeneration in Lama2-CMD.
2020-04-14 | GSE126416 | GEO