{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:24:42Z","timestamp":1782908682788,"version":"3.54.5"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Hereditary myopathy with lactic acidosis due to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency is a rare disorder of energy metabolism characterized clinically by myopathy with exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes. ISCU protein plays an important role in iron-sulphur clusters (Fe-S) assembly and is therefore essential for the activity of mitochondrial Fe-S proteins such as succinate dehydrogenase and aconitase. Recessive hypomorphic <jats:italic>ISCU<\/jats:italic> alleles have been associated with hereditary myopathy with lactic acidosis, also known as Swedish-type myopathy. To date, only one heterozygous dominant variant (c.287G&amp;gt;T, p.Gly96Val) in the ISCU gene has been reported as pathogenic. Functional studies have shown that this variant has a detrimental, dominant effect on activity of Fe-S-dependent enzymes. Whole exome sequencing performed in an adult female patient with progressive muscle weakness led to the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU gene. This variant is localized in the functional IscU_like domain of the ISCU protein, with bioinformatics prediction of damaging effects on protein function. Moreover, the same variant was also found in a few family members, who present signs of myopathy. This novel variant segregates with the disease and results in a phenotype reminiscent of the recessive disease previously reported. Yeast <jats:italic>Saccharomyces cerevisiae<\/jats:italic> is a widely used tool able to assess the impact of the VUS in a quick and efficient way, therefore functional studies were performed on this model system. The results obtained not only confirm the pathogenetic effect of the variant, but also support its dominant inheritance.<\/jats:p>","DOI":"10.3389\/fgene.2025.1605440","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T08:53:53Z","timestamp":1748854433000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Autosomal dominant myopathy caused by a novel ISCU variant"],"prefix":"10.3389","volume":"16","author":[{"given":"Joanna M.","family":"Rusecka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Ceccatelli Berti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Szcz\u0119\u015bniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Bednarska-Makaruk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Mroczek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena M.","family":"Kacprzak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Sobczy\u0144ska-Tomaszewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Goffrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"B1","article-title":"Calpainopathy","volume-title":"GeneReviews\u00ae","author":"Angelini","year":"1993"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6006","DOI":"10.3390\/ijms22116006","article-title":"Molecular details of the frataxin\u2013scaffold interaction during mitochondrial Fe\u2013S cluster assembly","volume":"22","author":"Campbell","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1002\/humu.24210","article-title":"Bi\u2010allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease","volume":"42","author":"Cappuccio","year":"2021","journal-title":"Hum. Mutat."},{"key":"B4","doi-asserted-by":"publisher","first-page":"300","DOI":"10.3390\/genes12020300","article-title":"The power of yeast in modelling human nuclear mutations associated with mitochondrial diseases","volume":"12","author":"Ceccatelli Berti","year":"2021","journal-title":"Genes"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1093\/hmg\/ddae104","article-title":"Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases","volume":"33","author":"Figuccia","year":"2024","journal-title":"Hum. Mol. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e12846","DOI":"10.1111\/nan.12846","article-title":"Identification of a novel heterozygous DYSF variant in a large family with a dominantly-inherited dysferlinopathy","volume":"48","author":"Folland","year":"2022","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1038\/s41467-019-09989-y","article-title":"Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism","volume":"10","author":"Fox","year":"2019","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nprot.2007.13","article-title":"High-efficiency yeast transformation using the LiAc\/SS carrier DNA\/PEG method","volume":"2","author":"Gietz","year":"2007","journal-title":"Nat. Protoc."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1172\/JCI115422","article-title":"Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect","volume":"88","author":"Haller","year":"1991","journal-title":"J. Clin. Invest"},{"key":"B10","volume-title":"Methods in yeast genetics: a cold spring harbor laboratory course manual","author":"Kaiser","year":"1994"},{"key":"B11","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.nmd.2009.09.011","article-title":"Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy","volume":"19","author":"Kollberg","year":"2009","journal-title":"Neuromuscul. Disord."},{"key":"B12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.nmd.2010.11.010","article-title":"Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron\u2013sulphur cluster deficiency myopathy","volume":"21","author":"Kollberg","year":"2011","journal-title":"Neuromuscul. Disord."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2170","DOI":"10.1093\/brain\/awp152","article-title":"Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy","volume":"132","author":"Kollberg","year":"2009","journal-title":"Brain"},{"key":"B14","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1136\/jnnp.27.5.361","article-title":"Hereditary metabolic myopathy with paroxysmal myoglobinuria due to abnormal glycolysis","volume":"27","author":"Larsson","year":"1964","journal-title":"J. Neurology, Neurosurg. and Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1136\/jmedgenet-2017-104822","article-title":"A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy","volume":"54","author":"Legati","year":"2017","journal-title":"J. Med. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.ajhg.2007.12.012","article-title":"Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance","volume":"82","author":"Mochel","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s00439-010-0931-3","article-title":"Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice","volume":"129","author":"Nordin","year":"2011","journal-title":"Hum. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1093\/hmg\/ddn057","article-title":"Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect","volume":"17","author":"Olsson","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/mgg3.413","article-title":"PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis","volume":"6","author":"Rawcliffe","year":"2018","journal-title":"Mol. Genet. Genomic Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and Genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1093\/emboj\/19.21.5692","article-title":"Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells","volume":"19","author":"Tong","year":"2000","journal-title":"EMBO J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.cmet.2006.02.003","article-title":"Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis","volume":"3","author":"Tong","year":"2006","journal-title":"Cell Metab."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1605440\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T08:53:54Z","timestamp":1748854434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1605440\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,2]]},"references-count":22,"alternative-id":["10.3389\/fgene.2025.1605440"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1605440","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,2]]},"article-number":"1605440"}}