Genotyping of autosomal recessive type of limb-girdle muscular dystrophies
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Janis Stavusis
PROVIDER: E-MTAB-4662 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes expressing alkaline phosphatase. They have been shown to ameliorate muscular dystrophies (currently incurable diseases) in different animal models and are now undergoing clinical experimentation for Duchenne muscular dystrophy. We show here that patients affected by limb-girdle muscular dystrophy 2D (LGMD2D, characterized by M-NM-1-sarcoglycan deficit) have a reduction of this subset of pericytes and hence mesoangioblast could not be derived for cell therapy. Therefore, we reprogrammed LGMD2D fibroblasts and myoblasts to induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from them. These cells can be expanded and genetically corrected with a muscle-specific lentiviral vector expressing human M-NM-1-sarcoglycan. Upon transplantation into ad hoc generated M-NM-1-sarcoglycan-null immunodeficient mice, they generate myofibers expressing M-NM-1-sarcoglycan. This approach may be useful for muscular dystrophies that show a reduction of resident progenitors and provides evidence of pre-clinical safety and efficacy of disease-specific iPSCs. 9 samples analyzed: 3 WT HIDEMs, 3 Limb-girdle muscular dystrophy 2D (LGMD2D) HIDEMs and 3 WT adult skeletal muscle derived mesoangioblasts (controls).
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Project description:Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (a-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of a-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes. FKRP deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell-derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. Additionally, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis.
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Project description:Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes expressing alkaline phosphatase. They have been shown to ameliorate muscular dystrophies (currently incurable diseases) in different animal models and are now undergoing clinical experimentation for Duchenne muscular dystrophy. We show here that patients affected by limb-girdle muscular dystrophy 2D (LGMD2D, characterized by α-sarcoglycan deficit) have a reduction of this subset of pericytes and hence mesoangioblast could not be derived for cell therapy. Therefore, we reprogrammed LGMD2D fibroblasts and myoblasts to induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from them. These cells can be expanded and genetically corrected with a muscle-specific lentiviral vector expressing human α-sarcoglycan. Upon transplantation into ad hoc generated α-sarcoglycan-null immunodeficient mice, they generate myofibers expressing α-sarcoglycan. This approach may be useful for muscular dystrophies that show a reduction of resident progenitors and provides evidence of pre-clinical safety and efficacy of disease-specific iPSCs.
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Project description:Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of progressive and genetic neuromuscular disorders that involve weakness and wasting of predominantly pelvic and shoulder girdle muscles. More than 30 subtypes have been identified, with variable phenotype. In the early stages of the disease, these LGMD share common clinical and histopathological characteristics among different subtypes and with other neuromuscular disorders, complicating the disease-subtype identification and thus, lengthening the final diagnosis of the disease. In the present study, we try to identify by a non-invasive method a molecular signature including biochemical and epigenetic parameters with a potential value for LGMD patient prognosis and stratification. Circulating miRNome was obtained by smallRNA-seq in plasma samples from LGMD patients (n=6) and matched controls (n=6). Over-representation analysis (ORA) using GO terms and KEGG database was used to study the functional enrichment of target genes. Biochemical parameters related to calcium metabolism, hormonal status, and muscle metabolism were also analyzed in these patients. Thirteen differentially expressed miRs (FDR < 0.05) were able to separate each clinical group by hierarchical clustering. Indeed, most of differentially expressed miRs were up-regulated. Functional enrichment analysis of the target genes for the dysregulated miRs revealed that targets of up-regulated miRs modulated cell cycle and cancer related pathways, while targets of down-regulated miRs were involved in muscle tissue development, regeneration and senescence. Four of the circulating miRs (miR-19b-3p, miR-192-5p, miR-122-5p and miR 323-3p) were further validated by qPCR in LGMD and in the more frequent muscular dystrophies: Duchenne (DMD)(n=5) and facioscapulohumeral muscular dystrophy (FSHD)(n=4). Receiver operating characteristic curve analysis revealed high AUC values for selected miRs (1.0 for miR-19b-3p, miR-192-5p and miR-122-5p; 0.75 for miR-323-3p) suggesting that these miRs could be good biomarker candidates for LGMD. The covariates gender, age at disease onset, and ambulation did not correlate with the expression levels of these miRs. However, differential expression of miR-122-5p (≥10-60 fold, p< 0.0001), miR-192-5p (≥10-60 fold, p< 0.0001) and miR-323-3p (≤ 2-10 fold, p<0.05) levels compared to matched controls could discriminate LGMD from DMD or FSHD dystrophies. In addition, a strong correlation between some of these circulating miRs and biochemical variables such as CK, vitamin D3, ALP and PTH was found only in LGMD patients.
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