Molecular and cellular basis of genetically inherited skeletal muscle disorders

Dowling, James J.; Weihl, Conrad C.; Spencer, Melissa J.

doi:10.1038/s41580-021-00389-z

Cited by 65 publications

(55 citation statements)

References 265 publications

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“… 1 , 2 , 3 MDs are a group of approximately 50 severe, debilitating monogenic disorders leading to a progressive inability to use muscles for daily activities up to the dependence on respiratory support in some patients. 4 So far, treatment consists of supportive measures, but correcting the underlying genetic defect in a sufficient number of cells in muscles would be a cure.…”

Section: Introductionmentioning

confidence: 99%

mRNA-mediated delivery of gene editing tools to human primary muscle stem cells

Stadelmann

Francescantonio

Marg

et al. 2022

Molecular Therapy - Nucleic Acids

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Section: Introductionmentioning

confidence: 99%

mRNA-mediated delivery of gene editing tools to human primary muscle stem cells

Stadelmann

Francescantonio

Marg

et al. 2022

Molecular Therapy - Nucleic Acids

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“…Mutations in dystrophin manifest in progressive skeletal muscle atrophy in young boys aged 3–5 years, who oftentimes become wheelchair dependent by early adolescence and ultimately succumb to untimely death ( Yiu and Kornberg, 2015 ). The dystrophin gene encodes for a structural protein, which connects the muscle cell membrane to the extracellular matrix, thus providing stabilization during muscle contractions ( Dowling et al., 2021 ). In the absence of DYSTROPHIN, muscle contractions expedite muscle breakage accompanied by rapid cycles of degeneration and regeneration, precipitating loss of myofibers and consequently replacement with fat and fibrotic tissues over time ( Dowling et al., 2021 ; Yiu and Kornberg, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 editing of directly reprogrammed myogenic progenitors restores dystrophin expression in a mouse model of muscular dystrophy

et al. 2022

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Genetic mutations in dystrophin manifest in Duchenne muscular dystrophy (DMD), the most commonly inherited muscle disease. Here, we report on reprogramming of fibroblasts from two DMD mouse models into induced myogenic progenitor cells (iMPCs) by MyoD overexpression in concert with small molecule treatment. DMD iMPCs proliferate extensively, while expressing myogenic stem cell markers including Pax7 and Myf5. Additionally, DMD iMPCs readily give rise to multinucleated myofibers that express mature skeletal muscle markers; however, they lack DYSTROPHIN expression. Utilizing an exon skipping-based approach with CRISPR/Cas9, we report on genetic correction of the dystrophin mutation in DMD iMPCs and restoration of protein expression in vitro. Furthermore, engraftment of corrected DMD iMPCs into the muscles of dystrophic mice restored DYSTROPHIN expression and contributed to the muscle stem cell reservoir. Collectively, our findings report on a novel in vitro cellular model for DMD and utilize it in conjunction with gene editing to restore DYSTROPHIN expression in vivo.

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“…Although heterogeneous, the CMDs can be classified by the cellular localization and function of the affected proteins. For example, pathogenic variants in extracellular matrix proteins have been identified (e.g., collagen VI (MIM:120220, 120240, 120250) and laminin α2 (MIM:156225), the extracellular matrix and cytoskeleton anchor dystrophin (MIM: 300376 and 310200), the cell surface dystrophin‐associated glycoprotein dystroglycan (DAG1, MIM: 616538 and 613818), glycosyltransferases (POMT1 (MIM: 607423), POMT2 (MIM: 607439)) and those of the nuclear envelope and cytoskeleton (Lamin A/C (MIM:150330)) (Schorling et al , 2017 ; Dowling et al , 2021 ). Very recently, variants affecting components of membrane trafficking machinery (TRAPPC11 (MIM:614138) and GOSR2 (MIM:604027)) have been added to the list of inherited CMDs (Larson et al , 2018 ; Henige et al , 2021 ; Stemmerik et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy

et al. 2021

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BET1 is required, together with its SNARE complex partners GOSR2, SEC22b, and Syntaxin‐5 for fusion of endoplasmic reticulum‐derived vesicles with the ER‐Golgi intermediate compartment (ERGIC) and the cis‐Golgi. Here, we report three individuals, from two families, with severe congenital muscular dystrophy (CMD) and biallelic variants in BET1 (P1 p.(Asp68His)/p.(Ala45Valfs*2); P2 and P3 homozygous p.(Ile51Ser)). Due to aberrant splicing and frameshifting, the variants in P1 result in low BET1 protein levels and impaired ER‐to‐Golgi transport. Since in silico modeling suggested that p.(Ile51Ser) interferes with binding to interaction partners other than SNARE complex subunits, we set off and identified novel BET1 interaction partners with low affinity for p.(Ile51Ser) BET1 protein compared to wild‐type, among them ERGIC‐53. The BET1/ERGIC‐53 interaction was validated by endogenous co‐immunoprecipitation with both proteins colocalizing to the ERGIC compartment. Mislocalization of ERGIC‐53 was observed in P1 and P2’s derived fibroblasts; while in the p.(Ile51Ser) P2 fibroblasts specifically, mutant BET1 was also mislocalized along with ERGIC‐53. Thus, we establish BET1 as a novel CMD/epilepsy gene and confirm the emerging role of ER/Golgi SNAREs in CMD.

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Molecular and cellular basis of genetically inherited skeletal muscle disorders

Cited by 65 publications

References 265 publications

mRNA-mediated delivery of gene editing tools to human primary muscle stem cells

mRNA-mediated delivery of gene editing tools to human primary muscle stem cells

CRISPR/Cas9 editing of directly reprogrammed myogenic progenitors restores dystrophin expression in a mouse model of muscular dystrophy

BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy

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