{"doi":"10.1016/j.stemcr.2021.09.009","title":"Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies","abstract":"Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-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 α-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. In addition, 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.","journal":"Stem Cell Reports","year":2021,"id":183000,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":736063,"name":"Cláudia Bincoletto","orcid":"0000-0001-6666-3673","position":1,"is_corresponding":false},{"id":712339,"name":"Neha R. Dhoke","orcid":null,"position":2,"is_corresponding":false},{"id":340374,"name":"Sridhar Selvaraj","orcid":"0000-0002-9736-8391","position":3,"is_corresponding":false},{"id":366156,"name":"Alessandro Magli","orcid":"0000-0003-3874-2838","position":4,"is_corresponding":false},{"id":227985,"name":"Haowen Zhou","orcid":"0000-0001-9678-1865","position":5,"is_corresponding":false},{"id":492161,"name":"Do‐Hyung Kim","orcid":"0000-0002-2924-4370","position":6,"is_corresponding":false},{"id":227993,"name":"Anne G. Bang","orcid":"0000-0002-1174-9258","position":7,"is_corresponding":false},{"id":340375,"name":"Rita C. R. Perlingeiro","orcid":"0000-0001-9412-1118","position":8,"is_corresponding":false},{"id":364280,"name":"Carolina Ortiz‐Cordero","orcid":"0000-0001-6953-0366","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:48:17.816498Z","pmid":"34653404","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}