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HomeNatureGenetic suppression features ABHD18 as a Barth syndrome therapeutic target

Genetic suppression features ABHD18 as a Barth syndrome therapeutic target

  • Schlame, M. & Xu, Y. The function of tafazzin, a mitochondrial phospholipid-lysophospholipid acyltransferase. J. Mol. Biol. 432, 5043–5051 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schlame, M. & Ren, M. Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett. 580, 5450–5455 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • Hornby, B. et al. Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome. Orphanet J. Rare Dis. 17, 336 (2022).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, A. Y., Vernon, H., Manuel, R., Almuqbil, M. & Hornby, B. Quality of life in Barth syndrome. Ther. Adv. Rare Dis. 3, 26330040221093743 (2022).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sabbah, H. N., Taylor, C. & Vernon, H. J. Temporal evolution of the heart failure phenotype in Barth syndrome and treatment with elamipretide. Future Cardiol. 19, 211–225 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Taylor, C. et al. Clinical presentation and natural history of Barth syndrome: an overview. J. Inherit. Metab. Dis. 45, 7–16 (2022).

    PubMed 

    Google Scholar
     

  • Wang, S. et al. Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome. Hum. Mol. Genet. 32, 2055–2067 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Q. & Han, X. Cardiolipin remodeling in diabetic heart. Chem. Phys. Lipids 179, 75–81 (2014).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, S. et al. Cardiolipin remodeling defects impair mitochondrial architecture and function in a murine model of Barth syndrome cardiomyopathy. Circ. Heart Fail. https://doi.org/10.1161/CIRCHEARTFAILURE.121.008289 (2021).

  • Whited, K., Baile, M. G., Currier, P. & Claypool, S. M. Seven functional classes of Barth syndrome mutation. Hum. Mol. Genet. 22, 483–492 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Anzmann, A. F. et al. Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules. J. Biol. Chem. 297, 101005 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Costanzo, M. et al. Global genetic networks and the genotype-to-phenotype relationship. Cell 177, https://doi.org/10.1016/j.cell.2019.01.033 (2019).

  • Chen, R. et al. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat. Biotechnol. 34, 531–538 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Pu, W. T. Experimental models of Barth syndrome. J. Inherit. Metab. Dis. 45, 72–81 (2022).

    PubMed 

    Google Scholar
     

  • Aregger, M. et al. Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism. Nat. Metab. 2, https://doi.org/10.1038/s42255-020-0211-z (2020).

  • Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Mair, B. et al. Essential gene profiles for human pluripotent stem cells identify uncharacterized genes and substrate dependencies. Cell Rep. 27, 599–615 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bachovchin, D. A. & Cravatt, B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov. 11, 52–68 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morgenstern, M. et al. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell Metab. 33, 2464–2483 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Price, T. R. et al. Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin. PLoS Genet. 19, e1010713 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Long, J. Z. & Cravatt, B. F. The metabolic serine hydrolases and their functions in mammalian physiology and disease. Chem. Rev. 111, 6022–6063 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brandner, K. et al. Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth syndrome. Mol. Biol. Cell 16, 5202–5214 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Le, C. H. et al. Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria. J. Biol. Chem. 295, 12485–12497 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seneviratne, A. K. et al. The mitochondrial transacylase, tafazzin, regulates for AML stemness by modulating intracellular levels of phospholipids. Cell Stem Cell 24, 621–636 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beranek, A. et al. Identification of a cardiolipin-specific phospholipase encoded by the gene CLD1 (YGR110W) in yeast. J. Biol. Chem. 284, 11572–11578 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang, Y. et al. Cardiac metabolic pathways affected in the mouse model of Barth syndrome. PLoS ONE 10, e0128561 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kutschka, I. et al. Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome. Basic Res. Cardiol. 118, 47 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, O., Chinni, B. K., Manlhiot, C. & Vernon, H. J. FGF21 and GDF15 are elevated in Barth syndrome and are correlated to important clinical measures. Mol. Genet. Metab. 140, 107676 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Tung, C. et al. Elamipretide: a review of its structure, mechanism of action, and therapeutic potential. Int. J. Mol. Sci. 26, https://doi.org/10.3390/ijms26030944 (2025).

  • Bononi, G., Tuccinardi, T., Rizzolio, F. & Granchi, C. α/β-Hydrolase domain (ABHD) inhibitors as new potential therapeutic options against lipid-related diseases. J. Med. Chem. 64, 9759–9785 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ben Ali, Y. et al. Use of an inhibitor to identify members of the hormone-sensitive lipase family. Biochemistry 45, 14183–14191 (2006).

    PubMed 

    Google Scholar
     

  • Duncan, A. L. Monolysocardiolipin (MLCL) interactions with mitochondrial membrane proteins. Biochem. Soc. Trans. 48, 993–1004 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burkhalter, M. D. et al. Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis. J. Clin. Invest. 129, 2841–2855 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lonsdale, J. et al. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

    CAS 

    Google Scholar
     

  • Ghandi, M. et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature 569, 503–508 (2019).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lesurf, R. et al. Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. npj Genom. Med. 7, 18 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Carney, O. S. et al. Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome. Hum. Mol. Genet. 34, 101–115 (2024).

  • Ye, C. et al. Deletion of the cardiolipin-specific phospholipase Cld1 rescues growth and life span defects in the tafazzin mutant: implications for Barth syndrome. J. Biol. Chem. 289, 3114–3125 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • Tyurina, Y. Y. et al. Lipidomics characterization of biosynthetic and remodeling pathways of cardiolipins in genetically and nutritionally manipulated yeast cells. ACS Chem. Biol. 12, 265–281 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Dudek, J. et al. Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. Stem Cell Res 11, 806–819 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • McKenzie, M., Lazarou, M., Thorburn, D. R. & Ryan, M. T. Mitochondrial respiratory chain supercomplexes are destabilized in Barth syndrome patients. J. Mol. Biol. 361, 462–469 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • Zong, S. et al. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Res 28, 1026–1034 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Musatov, A. & Robinson, N. C. Bound cardiolipin is essential for cytochrome c oxidase proton translocation. Biochimie 105, https://doi.org/10.1016/j.biochi.2014.07.005 (2014).

  • Sedlák, E. & Robinson, N. C. Destabilization of the quaternary structure of bovine heart cytochrome c oxidase upon removal of tightly bound cardiolipin. Biochemistry 54, https://doi.org/10.1021/acs.biochem.5b00540 (2015).

  • Benegiamo, G. et al. COX7A2L genetic variants determine cardiorespiratory fitness in mice and human. Nat. Metab. 4, 1336–1351 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pérez-Pérez, R. et al. COX7A2L is a mitochondrial complex III binding protein that stabilizes the III2+IV supercomplex without affecting respirasome formation. Cell Rep. 16, 2387–2398 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cogliati, S. et al. Mechanism of super-assembly of respiratory complexes III and IV. Nature 539, 579–582 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • Mair, B., Aregger, M., Tong, A. H. Y., Chan, K. S. K. & Moffat, J. A method to map gene essentiality of human pluripotent stem cells by genome-scale CRISPR screens with inducible Cas9. Methods Mol. Biol. 2377, 1–27 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brockmann, M. et al. Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. Nature 546, 307–311 (2017).

    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, https://doi.org/10.14806/ej.17.1.200 (2011).

  • Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hart, T. et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163, 1515–1526 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • Herzog, K. et al. Lipidomic analysis of fibroblasts from Zellweger spectrum disorder patients identifies disease-specific phospholipid ratios. J. Lipid Res. 57, 1447–1454 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chambers, M. C. et al. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 30, 918–920 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sumner, L. W. et al. Proposed minimum reporting standards for chemical analysis. Metabolomics 3, 211–221 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pinault, M. et al. A 1D high performance thin layer chromatography method validated to quantify phospholipids including cardiolipin and monolysocardiolipin from biological samples. Eur. J. Lipid Sci. Technol. 122, 1900240 (2020).

    CAS 

    Google Scholar
     

  • Plekhanov, A. Y. Rapid staining of lipids on thin-layer chromatograms with amido black 10B and other water-soluble stains. Anal. Biochem. 271, 186–187 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • Jha, P., Wang, X. & Auwerx, J. Analysis of mitochondrial respiratory chain supercomplexes using blue native polyacrylamide gel electrophoresis (BN-PAGE). Curr. Protoc. Mouse Biol. 6, 1–14 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Aken, B. L. et al. Ensembl 2017. Nucleic Acids Res. 45, D635–D642 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fonslow, B. R. et al. Digestion and depletion of abundant proteins improves proteomic coverage. Nat. Methods 10, 54–56 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • Washburn, M. P., Wolters, D. & Yates, J. R. III Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat. Biotechnol. 19, 242–247 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • He, L., Diedrich, J., Chu, Y. Y. & Yates, J. R. 3rd Extracting accurate precursor information for tandem mass spectra by RawConverter. Anal. Chem. 87, 11361–11367 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, T. et al. ProLuCID: an improved SEQUEST-like algorithm with enhanced sensitivity and specificity. J. Proteomics 129, 16–24 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tabb, D. L., McDonald, W. H. & Yates, J. R. III DTASelect and Contrast: tools for assembling and comparing protein identifications from shotgun proteomics. J. Proteome Res. 1, 21–26 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, J. et al. CIMAGE2.0: an expanded tool for quantitative analysis of activity-based protein profiling (ABPP) data. J. Proteome Res. 20, 4893–4900 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790–795 (2010).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, S. et al. AAV gene therapy prevents and reverses heart failure in a murine knockout model of Barth syndrome. Circ. Res. 126, 1024–1039 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ren, M. et al. Extramitochondrial cardiolipin suggests a novel function of mitochondria in spermatogenesis. J. Cell Biol. 218, 1491–1502 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Molenaars, M. et al. Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation. Dis. Model. Mech. 14, https://doi.org/10.1242/dmm.047746 (2021).

  • Kulik, W. et al. Bloodspot assay using HPLC–tandem mass spectrometry for detection of Barth syndrome. Clin. Chem. 54, 371–378 (2008).

  • van der Sande, M. et al. Seq2science: an end-to-end workflow for functional genomics analysis. PeerJ 11, e16380 (2023).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S., Zhou, Y., Chen, Y. & Gu, J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frölich, S., van der Sande, M., Schäfers, T. & van Heeringen, S. J. genomepy: genes and genomes at your fingertips. Bioinformatics 39, https://doi.org/10.1093/bioinformatics/btad119 (2023).

  • Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, L., Wang, S. & Li, W. RSeQC: quality control of RNA-seq experiments. Bioinformatics 28, 2184–2185 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sayols, S., Scherzinger, D. & Klein, H. dupRadar: a Bioconductor package for the assessment of PCR artifacts in RNA-Seq data. BMC Bioinformatics 17, 428 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ewels, P., Magnusson, M., Lundin, S. & Käller, M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32, 3047–3048 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gertsenstein, M. & Nutter, L. M. J. Production of knockout mouse lines with Cas9. Methods 191, 32–43 (2021).

    CAS 
    PubMed 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eberhardt, J., Santos-Martins, D., Tillack, A. F. & Forli, S. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J. Chem. Inf. Model. 61, 3891–3898 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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