Specific Defects Research Articles

MID1-COMPLEMENTING ACTIVITY regulates cell proliferation and development via Ca2+ signaling in Marchantia polymorpha.

MID1-COMPLEMENTING ACTIVITY (MCA) is a land plant-specific, plasma membrane protein and Ca2+ signaling component that responds to exogenous mechanical stimuli, such as touch, gravity, and hypotonic-osmotic stress, in various plant species. MCA is essential for cell proliferation and differentiation during growth and development in rice (Oryza sativa) and maize (Zea mays). However, the mechanism by which MCA mediates cell proliferation and differentiation via Ca2+ signaling remains unknown. Here, we address this question using the liverwort Marchantia polymorpha. We show that the M. polymorpha MCA ortholog, MpMCA, is highly expressed in actively dividing regions, such as apical notches in the thalli and developing gametangiophores, and that MpMCA is a plasma membrane protein. In vivo Ca2+ imaging using a Ca2+ sensor (yellow cameleon) revealed that MpMCA is required for maintaining proper [Ca2+]cyt levels in the apical notch region, egg cells, and antheridium cells. Mpmca mutant plants showed severe cell proliferation and differentiation defects in the thalli, gametangiophores, and gametangia, resulting in abnormal development and unsuccessful fertilization. Furthermore, expression of the Arabidopsis MCA1 gene complemented most of the defects in the growth and development of the Mpmca mutant plants. Our findings indicate that MpMCA is an evolutionarily conserved Ca2+-signaling component that regulates cell proliferation and development across the life cycle of land plants.

A noncoding variant confers pancreatic differentiation defect and contributes to diabetes susceptibility by recruiting RXRA.

Human genetics analysis has identified many noncoding SNPs associated with diabetic traits, but whether and how these variants contribute to diabetes is largely unknown. Here, we focus on a noncoding variant, rs6048205, and report that the risk-G variant impairs the generation of PDX1+/NKX6-1+ pancreatic progenitor cells and further results in the abnormal decrease of functional β cells during pancreatic differentiation. Mechanistically, this risk-G variant greatly enhances RXRA binding and over-activates FOXA2 transcription, specifically in the pancreatic progenitor stage, which in turn represses NKX6-1 expression. Consistently, inducible FOXA2 overexpression could phenocopy the differentiation defect. More importantly, mice carrying risk-G exhibit abnormal pancreatic islet architecture and are more sensitive to streptozotocin or a high-fat diet to develop into diabetes eventually. This study not only identifies a causal noncoding variant in diabetes susceptibility but also dissects the underlying gain-of-function mechanism by recruiting stage-specific factors.

Exposure to drinking water pollutants and non-syndromic birth defects: a systematic review and meta-analysis synthesis

ObjectivesTo evaluate the association between drinking water pollutants and non-syndromic birth defects.DesignSystematic review and meta-analysis synthesis.Data sourcesA search of MEDLINE, EMBASE and Google Scholar was performed to review relevant citations...

14-3-3ε conditional knockout mice exhibit defects in the development of the epidermis.

The epidermis is a stratified epithelium that functions as the first line of defense against pathogenic invasion and acts as a barrier preventing water loss. In this study, we aimed to decipher the role of 14-3-3ε in the development of the epidermis. We report that loss of 14-3-3ε in the epidermis of juvenile and adult mice reduces cell division in the basal layer and increases the percentage of cells with multiple centrosomes, leading to a reduction in the thickness of the basal and stratified layers. We also demonstrate a decrease in the expression of differentiation markers, although no gross morphological defects in the skin or adverse effects on the survival of the mice were observed. These results suggest that loss of 14-3-3ε in the epidermis may lead to defects in proliferation and differentiation.

The effect of hereditary thrombophilia on recurrent pregnancy loss: a retrospective cohort study

ObjectiveThrombophilia screening has been performed in patients with conditions such as previous fetal death, (fetal growth restriction) FGR, preeclampsia, (hemolysis. elevated liver enzyme, low platelet count) HELLP Syndrome, previous abruptio placentae, previous thrombosis in pregnancy, and abnormal placental histology. The actual role of hereditary thrombophilia in recurrent pregnancy loss (RPL) is still debated. This study was intended to determine the incidence of specific gene defects for hereditary thrombophilia and to ascertain their impact on RPL in central Anatolia in Turkey.MethodsThis retrospective cohort study was performed between January 2012 and December 2022. All pregnant women with a complete hereditary screening profile were included. The investigated gene polymorphisms were methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, Factor V Leiden G1691A, and Factor II prothrombin G20210A. Cases of pregnant women at least two or more consecutive pregnancy losses before 22 weeks of gestation were defined as RPL. The rates of genetic screening and their association with RPL were analyzed.ResultsRPL was identified in 224 (27.58%) of the 812 pregnant women with complete genetic screening. Although there was no difference in terms of age, body mass index, numbers of ectopic pregnancies, molar pregnancies, or dilatation & curettage (p > 0.05), gravity (2.0 [2.0–3.0] vs. 4.0 [3.0–5.0]), parity (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), live birth (1.0 [1.0–2.0] vs. 1.0 [0–1.0]), anembryonic pregnancy (0 [0–0] vs. 0 [0–0]), miscarriage (0 [0–1.0] vs. 3.0 [2.0–3.0]), and stillbirth (0 [0–0] vs. 0 [0–0]) numbers differed significantly between the groups (p < 0.05). While no significant differences were determined in MTHFR A1298C, Factor V Leiden, factor II prothrombin G20210A, or homocysteine levels (p > 0.05), the homozygous MTHFR C677T positivity rates differed significantly (6.3% in the non-RPL group vs. 11.6% in the RPL group, p = 0.027) .ConclusionThe homozygous MTHFR C677T polymorphisms was found to be more frequent in women with RPL. Further studies with larger cohorts are needed to confirm our results.

Unmet needs in the management of hereditary angioedema from the perspective of Brazilian patients

IntroductionHereditary angioedema (HAE) is a rare genetic disease characterized by recurrent, potentially life-threatening angioedema episodes. Despite its severity, including the risk of asphyxiation, HAE often remains underdiagnosed. The disease significantly impacts patient quality of life (QoL), leading to anxiety, depression, and avoidance behaviors due to the unpredictable nature of attacks. Understanding the perspectives of patients is crucial for identifying unmet needs in managing this complex condition. ObjectiveThis study aimed to gather real-world insights from Brazilian patients with C1 inhibitor deficiency HAE to identify their unmet needs and assess their perceptions of the effectiveness of current care in preventing and treating HAE attacks. MethodsA cross-sectional study utilized a SurveyMonkey questionnaire distributed to HAE patients through ABRANGHE via email. Participants provided informed consent, and their responses were anonymous. The questionnaire, developed with input from experts and patients, covered aspects of HAE diagnosis, treatment experiences, and QoL assessments. ResultsThe survey included 178 HAE patients, predominantly female (81%), aged 30–50 years (58%), and college-educated (62%). The most common HAE defect was C1–INH deficiency (53%), followed by HAE-nC1INH (23%), with nearly a quarter unaware of their specific defect. Diagnosis delays were prevalent, with a significant number reporting 13–50 attacks annually (33%) and 15% experiencing more than 50 attacks per year. Laryngeal involvement was reported by 26% of respondents. Most patients (69%) attended regular follow-ups, with 72% on prophylactic treatment and 67% managing acute attacks. The most used acute treatment was Icatibant (49%), followed by pdC1INH (24%). However, confusion regarding medication use persisted, with 45% incorrectly believing that oral medications could effectively treat attacks. Key unmet needs identified included improved access to emergency rooms during attacks (73%), better availability of prophylactic treatment (69%), and enhanced access to specialized care (63%). Patients also emphasized the need for psychological support, increased awareness of HAE, and educational initiatives for patients and healthcare providers. DiscussionThis study highlighted significant challenges in HAE management among Brazilian patients, particularly concerning delayed diagnosis, misconceptions about treatment, and inadequate access to specialized care and prophylactic treatments. The high frequency of emergency room visits underscores the difficulties in managing the disease. The substantial burden of HAE on QoL emphasizes the urgent need for improved physician education, streamlined diagnostic processes, and equitable access to effective medications and specialized care facilities. Addressing these gaps is crucial to better support HAE patients, improve diagnostic timeliness, enhance treatment efficacy, and ultimately enhance the overall quality of life for individuals living with HAE.

Infections in Inborn Errors of STATs

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is highly conserved and essential for numerous biological functions triggered by extracellular signals, including cell proliferation, metabolism, immune response, and inflammation. Defects in STATs, either loss-of-function or gain-of-function defects, lead to a broad spectrum of clinical phenotypes in humans, including a wide range of infectious complications. The susceptibility to pathogens can stem from defects in immune cells within the hematopoietic compartment, impaired barrier functions of non-hematopoietic compartment, or a combination of both, depending on the specific STAT defect as well as the pathogen exposure history. Effective management involves antimicrobial prophylaxis tailored to the patient’s infection risk and improving disease control with targeted therapies and/or hematopoietic cell transplantation.

Middle Ear Malformations

Middle ear malformations (MEMs) represent a diverse group of congenital anomalies with significant implications for auditory function. These malformations, which occur in approximately 0.5 to 3% of conductive hearing loss cases, can arise from various genetic and environmental factors. They often manifest unilaterally and may occur in isolation or as part of a syndromic condition. MEMs are closely associated with abnormalities of the external ear and less frequently with inner ear anomalies.Embryologically, the middle ear develops from the first and second pharyngeal arches, with interactions between the ectoderm and endoderm contributing to the formation of essential structures such as the tympanic membrane, ossicles and Eustachian tube. Disruptions in these developmental processes can lead to a spectrum of MEMs, ranging from minor defects to severe malformations affecting multiple middle ear components.Clinical management of MEMs requires a multidisciplinary approach, involving otolaryngologists, pediatricians, and audiologists. Early intervention with appropriate hearing aids, including conventional hearing aids and bone conduction devices, is essential to mitigate the impact of conductive hearing loss on speech and language development, particularly in children.Surgical planning involves comprehensive preoperative assessment, including high-resolution computed tomography imaging to evaluate middle ear anatomy, the facial nerve course, and vascular anomalies. Traditional surgical approaches such as stapesplasty and tympanoplasty remain mainstays for correcting specific middle ear defects, while advances in technology have expanded the role of active middle ear implants in treating special cases.In conclusion, MEMs represent a heterogeneous group of congenital anomalies with diverse etiologies and clinical implications. A thorough understanding of their embryological basis, genetic underpinnings, and surgical management strategies is crucial for optimizing outcomes in affected individuals.

Flow Profiles Identify Sources of Poor Metered Dose Inhaler Technique: An observational study in long-term pMDI users

BackgroundInhaled medications are commonly used as therapy for obstructive lung disease (OLD) yet poor technique from pressurized metered dose inhalers (pMDI) can severely limit drug delivery and therapeutic efficacy. A novel flow sensor has been developed to characterize inhalation flow profiles from pMDIs. Research QuestionAmong OLD subjects, flow profiles during pMDI inhalation maneuvers would expose poor patterns of pMDI use, which can be used to remediate pMDI technique. Study Design and MethodsA novel flow sensor was coupled to a placebo pMDI inhaler to characterize inhalation technique in 70 OLD participants from a pulmonary clinic. pMDI inhalation flow profiles generated actuation timing, mean inspiratory airflow (MIF) and inspired volume before and after visualizing these features. McNemar’s was used to characterize the impact of training on pMDI inhalation metrics. The post-actuation inspired volume was normalized to inspiratory capacity (IC). ResultsAmong participants with 17.4 (SD = 17.9) years of pMDI use, flow profiles uncovered mistimed actuations in 47.1% and poor inspiratory flow rates in 30.0% of subjects. After visualizing flow profiles, participants improved actuation timing (c2(1) =12.042, p < .001), mean inhaled volume (87.9 to 105.6% of IC, p<0.001) and the combined inhalation metrics (c2(1) =8.45, p = 0.003). InterpretationFlow profiles helped uncover and remediate specific defects in pMDI technique in the majority of chronic OLD users. Flow profiles from inhaled medications can be used to enhance drug delivery to the lung.

Linear dielectric ceramics for near-zero loss high-capacitance energy storage

High energy-density (Wrec) dielectric capacitors have gained a focal point in the field of power electronic systems. In this study, high energy storage density materials with near-zero loss were obtained by constructing different types of defect dipoles in linear dielectric ceramics. Mg2+and Nb5+ are strategically chosen as acceptor/donor ions, effectively replacing Ti4+ within Ca0.5Sr0.5TiO3-based ceramics. The results indicate that under an applied electric field, specific defects such as [MgTi″−VO··] and [NbTi·−Ti3+], can effectively regulate VO·· and electron movement, significantly reducing losses. Furthermore, high-density insulating grain boundaries, reduced VO·· concentrations and diminished carrier mobility contribute to enhanced resistivity, resulting in high Wrec ∼7.62 J/cm3 and η ∼92 % at 640 kV/cm, making it one of the most promising linear dielectrics to date. Notably, Wrec and η remain remarkably stable across a broad range of frequencies (1–500 Hz), temperatures (25–175 °C) and numerous cycles (up to 106). Additionally, finite element software was used to simulate the distribution of dielectric constant, electric potential, and local electric field, further verifying the correlation between microstructure and breakdown resistance. This innovative work provides a sustainable strategy to optimize the energy storage capacity of lead-free ceramics over a wide temperature range through strategic manipulation of defects.

A conserved Plasmodium nuclear protein is critical for late liver stage development

Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup—) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linup— parasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linup— liver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine.

A very simple synthesis of defect-rich PdAg nanosponges for highly selective hydrogenation of furfural

Furfuryl alcohol (FA) is an important chemical and has extensive applications in varied fields. To realize the highly selective hydrogenation of furfural (FF) to produce FA, the key is the preparation of the catalysts with excellent performance. Herein, a very simple wet chemical method is developed for the one-step preparation of PdAg nanosponges (NSs). Specifically, with Pd(OAc)2 and AgNO3 as precursors, and ethylene glycol (EG) as both solvent and reducing agent, PdAg NSs can be grown and assembled at mild temperature of 40 °C. Throughout the reaction, no any surfactants and additional reducing agents are applied. The as-prepared PdAg NSs possess 3D self-supported alloy structures, “clean” surface, abundant pores, high specific surface area and rich defects. In the FF hydrogenation reaction at 60 °C under 1.5 MPa H2 pressure in the mixed solvent of ethanol and water (1 : 4 in volume ratio), the self-supported PdAg-1 NSs (1 : 1 in Pd/Ag molar ratio) exhibit superior catalytic performance than other PdAg NSs, pure Pd sample and commercial Pd/C (10%). With PdAg-1 NSs as catalyst in the absence of support, 100% FF can be converted and the selectivity toward FA is as high as 97.1% at 36.0 h of reaction. After 4 cycles, PdAg-1 NSs still maintain the high catalytic activity in FF hydrogenation and high selectivity toward FA, which may originate from the 3D self-supported structures, high specific surface area, “clean” surface, rich defects and electronic synergistic effect between Pd and Ag. This simple fabrication of PdAg NSs introduces new ideas for the synthesis of other nanostructured bi- and multi-metallic catalysts for highly selective FF hydrogenation to FA and other advanced applications.

Exploring RNA therapeutics for urea cycle disorders.

RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.

Investigations of strength and quality of clinched joints using digital image correlation

ABSTRACT This study examines the impact of processing conditions on joint strength and the effectiveness of digital image correlation (DIC) in detecting failure points in clinched joints. Mechanical tests, including single-lap shear and pull-out tests, were conducted using DIC to evaluate joint quality in various clinched configurations. The results showed frequent failures at the neck rejoin in clinched joints between mild steel and aluminum sheets, particularly when thinner sheets were positioned on the punch side and softer materials on the die side. DIC effectively identified defects and failure locations, offering insights into material combinations, sheet positioning, and failure modes. Although DIC was useful in detecting defects in both elastic and destructive regions, its ability to distinguish specific defect types from strain contour maps was limited. The study highlights the need for further research to extend DIC’s application to other mechanical joining systems and advocates for its proactive use in refining designs and manufacturing processes.

Guided bone regeneration improves defect fill and reconstructive outcomes in 3-wall peri-implantitis defects.

This multi-center, randomized clinical trial compared the long-term outcomes of guided bone regeneration (GBR) with open flap debridement (OFD) in treating peri-implantitis-related bony defects with ≥3 osseous walls over 36 months. The study aimed to evaluate the healing potential of GBR using a deproteinized bovine bone mineral (DBBM) graft and native bilayer collagen membrane (NBCM) compared to OFD without the use of graft materials. Sixty-six individuals diagnosed with peri-implantitis were randomly assigned to either GBR (34 patients) or OFD (32 patients). The OFD group served as the control, where inflamed tissue was removed and the implant surface decontaminated using 3% hydrogen peroxide, but no bone graft was placed. The GBR group received DBBM and NBCM for defect reconstruction. Radiographic defect fill (RDF), probing pocket depth (PPD), bleeding on probing (BOP), suppuration (SUP), mucosal recession (MREC), and patient-reported outcomes (PROs) were assessed over the study duration. Post-surgical care included azithromycin, ibuprofen, and chlorhexidine rinses. The study involved baseline assessments, surgical interventions, and follow-ups at 6, 12, and 36 months. Supportive peri-implant therapy was provided every 3 months during the additional 24-month follow-up. Primary outcome was RDF at 36 months. Secondary outcomes included PPD, BOP, SUP, MREC, and PROs. Descriptive statistics and ANCOVA models were used for analysis. At 36 months, GBR resulted in a mean RDF of 2.13 ± 1.26 mm, compared to 1.64 ± 1.54 mm with OFD (p = .18). No significant differences were found in PPD, BOP, SUP, REC, or PROs between the groups. Treatment success (defined as no additional bone loss, PPD ≤ 5 mm, no BOP, and no SUP) was achieved in 46.2% of GBR cases and 20% of OFD cases (p = 0.053). GBR provided improved short-term defect fill and higher treatment success compared to OFD, although the differences were not statistically significant. Both procedures maintained clinical parameters over 36 months, with similar patient satisfaction (PROs) observed for GBR and OFD. The adjunct use of DBBM and NBCM may offer clinical benefits for peri-implantitis cases with specific bony defect morphology.

Advancing Graphene Imaging for Clear Identification of Lattice Defects: The Application of Revolve Sphere Levelling to Scanning Tunnelling Microscopy Images.

Application of revolve sphere levelling (RSL) as a practical and effective image processing tool for enhancing scanning tunnelling microscopy (STM) images of graphene atomic lattices is presented. Low-cost, ambient, and non-invasive STM methods overcome limitations of traditional imaging methods like scanning transmission electron microscopy (STEM) and transmission electron microscopy (TEM) that can introduce or alter defects in graphene. Utilizing high-quality graphene synthesized via Paragraf's patented Metal-Organic Chemical Vapor Deposition (MOCVD) method, RSL, which is easily implemented via the Gwyddion software package, effectively highlights the hexagonal lattice structure and specific defect structures. This provides clarity of the atomic structure that traditional methods struggle to achieve. This research emphasizes the utility of RSL in materials science for defect identification in graphene, and points to future research in optimizing RSL for a broader range of defects and applications in other 2D materials.

Short interbirth interval and adverse pregnancy outcomes: a Bayesian network approach

BackgroundInterbirth interval (IBI), the time between consecutive births, has been tied to perinatal outcomes. ObjectiveTo analyze adverse perinatal events following short IBI in a large South American sample. Study designObservational, retrospective, hospital-based study including malformed and nonmalformed live- and stillbirths. Outcomes were preterm birth (PTB), low birth weight (LBW), and specific birth defects. Logistic regressions were used to evaluate the risk of selected variables for short IBI and for adverse outcomes after short IBI, adjusting by confounders. Bayesian networks exhibited relationships among short IBI, outcomes, and variables. ResultsShort IBI rate was 2%–3%. Maternal age and a previous abortion were the main confounders. A significant high risk for short IBI was found in mothers ≤19 years while mothers ≥30 were at low risk, mediated by a previous abortion. The risk of short IBI, adjusted by confounders, was significant for LBW but not for PTB. An unadjusted risk of short IBI was observed for gastroschisis, which disappeared after adjusting for confounders. Maternal age ≤19 and previous abortion were directly related with gastroschisis; the relationship between gastroschisis and short IBI occurred through any of these two variables. A direct relationship between gastroschisis and maternal age ≥30 was observed. ConclusionsOnly young mothers were directly related with short IBI. In older mothers, a short IBI mainly occurred after a previous abortion. Short IBI was a risk factor only for LBW. The PTB and gastroschisis relationship with short IBI was indirect, mediated by young maternal age and/or a previous abortion.

Investigations on the leak resistance performance and the difference mechanism of composite materials under several typical curing processes

This study aims to investigate the leak resistance of carbon fiber composite products formed by various typical curing processes. Firstly, the leak rates of specimens produced through different curing methods were measured, and the defect were statistically analyzed. After that, the simulation approach was applied to numerically study the impact of these defect characteristics on leak rates was examined from the three factors of porosity, void distribution and void morphology, specimen with prefabricated defects was prepared, and its leak performance were tested to validate the simulation results. Finally, the differences in leak resistance among specimens under different curing processes were analyzed from the perspective of curing defects, and specific defect characteristics contributing to enhanced leak resistance were identified.

Emerging roles of cancer-associated histone mutations in genomic instabilities.

Epigenetic mechanisms often fuel the quick evolution of cancer cells from normal cells. Mutations or aberrant expressions in the enzymes of DNA methylation, histone post-translational modifications, and chromatin remodellers have been extensively investigated in cancer pathogenesis; however, cancer-associated histone mutants have gained momentum in recent decades. Next-generation sequencing of cancer cells has identified somatic recurrent mutations in all the histones (H3, H4, H2A, H2B, and H1) with different frequencies for various tumour types. Importantly, the well-characterised H3K27M, H3G34R/V, and H3K36M mutations are termed as oncohistone mutants because of their wide roles, from defects in cellular differentiation, transcriptional dysregulation, and perturbed epigenomic profiles to genomic instabilities. Mechanistically, these histone mutants impart their effects on histone modifications and/or on irregular distributions of chromatin complexes. Recent studies have identified the crucial roles of the H3K27M and H3G34R/V mutants in the DNA damage response pathway, but their impacts on chemotherapy and tumour progression remain elusive. In this review, we summarise the recent developments in their functions toward genomic instabilities and tumour progression. Finally, we discuss how such a mechanistic understanding can be harnessed toward the potential treatment of tumours harbouring the H3K27M, H3G34R/V, and H3K36M mutations.

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms.

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis.