FOXK2 in Skeletal Muscle Development: A New Pathogenic Gene for Congenital Myopathy with Ptosis
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ABSTRACT:
PROVIDER: PRJNA1234572 | ENA |
REPOSITORIES: ENA
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Project description:Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in six pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2-deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.
2025-07-01 | GSE291642 | GEO
Project description: Not available
| S-BSST1949 | biostudies-other
Project description: Not available
| S-SCDT-10_1038-S44321-025-00247-X | biostudies-other
Project description:Pathogenic variants in MTM1 are associated with a severe, congenital muscle disorder called X-linked myotubular myopathy. Here, we aimed to assess the effect of mavacamten (myosin ATPase inhibitor) treatment in a mouse model for X-linked myotubular myopathy (Mtm1-KO) using the global untargeted proteomics approach. We used skeletal muscle tissue from Mtm1-KO mice and from WT mice, both treated and not treated with mavacamten.
2025-10-31 | PXD068387 | Pride
Project description:Molecular characterization of collagen-VI related myopathies currently relies on standard sequencing, which yields a detection rate approximating 75-79% in Ullrich congenital muscular dystrophy (UCMD) and 60-65% in Bethlem myopathy (BM) patients as PCR-based techniques tend to miss gross genomic rearrangements as well as copy number variations (CNVs) in both the coding sequence and intronic regions. We have designed a custom oligonucleotide CGH array in order to investigate the presence of CNVs in the coding and non-coding regions of COL6A1, A2, A3, A5 and A6 genes and a group of genes functionally related to collagen VI. A cohort of 12 patients with UCMD/BM negative at sequencing analysis and 2 subjects carrying a single COL6 mutation whose clinical phenotype was not explicable by inheritance were selected and the occurrence of allelic and genetic heterogeneity explored. A deletion within intron 1A of the COL6A2 gene, occurring in compound heterozygosity with a small deletion in exon 28, previously detected by routine sequencing, was identified in a BM patient. RNA studies showed monoallelic transcription of the COL6A2 gene, thus elucidating the functional effect of the intronic deletion. No pathogenic mutations were identified in the remaining analyzed patients, either within COL6A genes, or in genes functionally related to collagen VI. Our custom CGH array may represent a useful complementary diagnostic tool, especially in recessive forms of the disease, when only one mutant allele is detected by standard sequencing. The intronic deletion we identified represents the first example of a pure intronic mutation in COL6A genes. Comparative Genomic Hybridization experiment. Experimental Replicates: twice
2010-01-27 | E-GEOD-20025 | biostudies-arrayexpress
Project description:Transcription profiling of FOXK2 expression in HeLa cells from a stably integrated doxycyline-inducible EGFP-FOXK2 expression construct.
2011-11-03 | E-MEXP-3040 | biostudies-arrayexpress
Project description:Chromatin immunoprecipitation of FOXK2 (tagged with Flag and His tags) in U2OS cells detected by SOLiD sequencing. ***Correction March 2014: The sample “FOXK2_Dox_treated” has been renamed, it was originally named “FOXK2_rep2”. A new sample “FOXK2_rep2” has been added, with new files. It has come to our attention that one of the FOXK2 ChIP-seq replicates 'FOXK2_rep2' that we used in our paper recent paper (Ji, Z., Donaldson, I.J., Liu, J., Hayes, A., Zeef, L.A.H. and Sharrocks, A.D. (2012) The forkhead transcription factor FOXK2 promotes AP-1-mediated transcriptional regulation. Mol. Cell. Biol. 32, 385-398. doi:10.1128/MCB.05504-11) was incorrect. The replicate was actually treated with doxorubicin prior to ChIP-seq analysis resulting in the loss of many FOXK2 binding events.***
2011-01-20 | E-MTAB-565 | biostudies-arrayexpress
Project description:<p>Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an <i>RYR1</i> variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. </p>
| phs001342 | dbGaP
Project description:Although clinically associated with severe intellectual disability, West syndrome, Dandy-Walker malformation, and syndactyly, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 acts as a transcription repressor. Strikingly, FOXK2 interacts with multiple transcription corepressor complexes including NCoR/SMRT, SIN3A, NuRD, and REST/CoREST. FOXK2 assembles these transcription programs to repress a cohort of genes including HIF1 and EZH2 and to regulate several signaling pathways including the hypoxic response that is critically implicated in tumor development and progression. We showed that FOXK2 inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses the growth and metastasis of breast cancer in vivo. Interestingly, FOXK2 is transactivated by ERand transrepressed via reciprocal successive feedback by HIF1/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, leading to elevated expression of EZH2, an eminent feature of aggressive breast cancer. Indeed, the expression of FOXK2 is inversely correlated with that of EZH2 and HIF1in breast carcinomas, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ER/PR/Her2 status, all indicators of poor prognosis. Our experiments revealed that FOXK2 is massively involved in transcription repression, providing a molecular basis for the understanding of the mechanistic action of FOXK2. Our study identified the ER-FOXK2-HIF1/EZH2 axis in breast cancer progression, supporting the pursuit of these molecules as therapeutic targets for breast cancer intervention.
2016-11-08 | GSE84241 | GEO