From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies

Sztretye, Mónika; Szabó, László Z.; Dobrosi, Nóra; Fodor, János; Szentesi, Péter; Almássy, János; Magyar, Zsuzsanna; Dienes, B.; Csernoch, László

doi:10.3390/ijms21238935

Cited by 17 publications

(10 citation statements)

References 251 publications

(221 reference statements)

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“…Several DM1 mouse models have been developed, but few recapitulate the multisystemic character of the disease, with DMSXL being one of them. 37 , 38 DMSXL mice are transgenic mice carrying the human DM1 locus with over 1,000 CTG repeats. Mice that carry both transgenes (homozygous; DMSXL) exhibit the majority of DM1 symptoms, whereas mice that have one (heterozygous) or no (wild type; WT) copy of the transgene do not show any of the DM1 symptomatology.…”

Section: Resultsmentioning

confidence: 99%

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1

Koutalianos

Koutsoulidou

Mytidou

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, primarily characterized by muscle wasting and weakness. Many biomarkers already exist in the rapidly developing biomarker research field that aim to improve patients’ care. Limited work, however, has been performed on rare diseases, including DM1. We have previously shown that specific microRNAs (miRNAs) can be used as potential biomarkers for DM1 progression. In this report, we aimed to identify novel serum-based biomarkers for DM1 through high-throughput next-generation sequencing. A number of miRNAs were identified that are able to distinguish DM1 patients from healthy individuals. Two miRNAs were selected, and their association with the disease was validated in a larger panel of patients. Further investigation of miR-223-3p, miR-24-3p, and the four previously identified miRNAs, miR-1-3p, miR-133a-3p, miR-133b-3p, and miR-206-3p, showed elevated levels in a DM1 mouse model for all six miRNAs circulating in the serum compared to healthy controls. Importantly, the levels of miR-223-3p, but not the other five miRNAs, were found to be significantly downregulated in five skeletal muscles and heart tissues of DM1 mice compared to controls. This result provides significant evidence for its involvement in disease manifestation.

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Section: Resultsmentioning

confidence: 99%

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1

Koutalianos

Koutsoulidou

Mytidou

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…Early recognition also offers opportunities for patients to enroll in clinical trials investigating new treatments, of which there are many in the research pipeline. [20][21][22] Patients with dystrophinopathies and co-occurring neurocognitive conditions should not miss out on these potentially life-changing interventions because of a preventable delay in diagnosis.…”

Section: Discussionmentioning

confidence: 99%

The Hidden Disease: Delayed Diagnosis in Duchenne Muscular Dystrophy and Co-Occurring Conditions

Lee

Turnage

Sutyla

et al. 2022

J Dev Behav Pediatr

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:Objective:Early diagnosis of Duchenne muscular dystrophy (DMD) is important for timely intervention to prolong function and preserve quality of life. The prevalence of various neurocognitive disorders is known to be higher in patients with DMD than the general population. In this study, we highlight cases of delayed DMD diagnosis that resulted from misattribution of early motor symptoms to co-occurring neurocognitive conditions. We also investigate the difference in age at DMD diagnosis in the setting of specific co-occurring neurocognitive conditions.Method:In this study, we reviewed 40 consecutive patients seen at a Certified Duchenne Care Center, excluding siblings of already-diagnosed patients. We highlight cases of significant delay in DMD diagnosis in the setting of co-occurring neurocognitive diagnoses. We also investigate the association of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability, and speech/language delay on age of DMD diagnosis.Results:The prevalence of co-occurring neurocognitive diagnoses was 73.1% in patients diagnosed at or after age 5 years vs. 35.7% in those diagnosed before age 5 years. The average age of DMD diagnosis was 6.6 years in patients with any co-occurring neurocognitive diagnoses and 4.9 years in patients without (p = 0.09). Individual analysis of ASD and ADHD showed significant differences. A greater number of co-occurring conditions were associated with an increased age at DMD diagnosis (R2 = 0.87, p < 0.001).Conclusion:The data suggest an association between the presence of co-occurring neurocognitive conditions and a later age of DMD diagnosis. One cost-effective diagnostic step that can be implemented by all pediatric practitioners is testing serum creatinine kinase (CK) in any child with motor delays or hypotonia, even in the context of other behavioral or cognitive disabilities.

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“…However, the underlying pathogenesis is still not clear and there is no effective treatment. Mouse models are essential tools for studying the pathogenic mechanism and developing therapeutic strategies for human muscular dystrophies and congenital myopathies ( Sztretye et al, 2020; van Putten et al, 2020 ). Here, we generated a LAMA2 -CMD mouse model by utilizing a CRISPR/Cas9 technology and based on the frequently observed disease-causing genetic variant in human patients.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype

Tan,

Liu,

Luo

et al. 2024

Preprint

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Understanding the underlying pathogenesis ofLAMA2-related muscular dystrophy (LAMA2-MD) have been hampered by lack of genuine mouse model. We created a newLama2knockout mouse (dyH/dyH) and reported here its close simulation to human neuropathology and symptoms. We first established thatLama2was predominantly expressed within the cortical surface of normal mouse brain, specifically, highly concentrated in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells with a modest presence within astrocytes. OurLama2knockout mice confirmed specific decreasedLama2expression in those cell types and resulted in disruption of gliovascular basal lamina assembly. This molecular pathogenesis mechanism was elucidated by a novel scRNA-seq. Furthermore, through transcriptomic investigation, these dyH/dyHmice were showed aberrant structure of muscle cytoskeletons which impaired normal muscle development and resulted in weakness. This is the first reported genuine model simulating humanLAMA2-MD. We can use it to study the molecular pathogenesis and develop effective therapies.

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From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies

Cited by 17 publications

References 251 publications

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1

The Hidden Disease: Delayed Diagnosis in Duchenne Muscular Dystrophy and Co-Occurring Conditions

A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype

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