{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:43:49Z","timestamp":1760143429085,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:00:00Z","timestamp":1707350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2018-12366314"],"award-info":[{"award-number":["RF-2018-12366314"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Serine\/arginine-rich splicing factors (SRSFs) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of SRSF proteins in regulating mitochondrial activity has already been shown for SRSF6, but SRSF4 altered expression has never been reported as a cause of bone marrow failure. An 8-year-old patient admitted to the hematology unit because of leukopenia, lymphopenia, and neutropenia showed a missense variant of unknown significance of the SRSF4 gene (p.R235W) found via whole genome sequencing analysis and inherited from the mother who suffered from mild leuko-neutropenia. Both patients showed lower SRSF4 protein expression and altered mitochondrial function and energetic metabolism in primary lymphocytes and Epstein\u2013Barr-virus (EBV)-immortalized lymphoblasts compared to healthy donor (HD) cells, which appeared associated with low mTOR phosphorylation and an imbalance in the proteins regulating mitochondrial biogenesis (i.e., CLUH) and dynamics (i.e., DRP1 and OPA1). Transfection with the wtSRSF4 gene restored mitochondrial function. In conclusion, this study shows that the described variant of the SRSF4 gene is pathogenetic and causes reduced SRSF4 protein expression, which leads to mitochondrial dysfunction. Since mitochondrial function is crucial for hematopoietic stem cell maintenance and some genetic bone marrow failure syndromes display mitochondrial defects, the SRSF4 mutation could have substantially contributed to the clinical phenotype of our patient.<\/jats:p>","DOI":"10.3390\/ijms25042083","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T09:00:02Z","timestamp":1707382802000},"page":"2083","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant of the SRSF4 Gene"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-1704","authenticated-orcid":false,"given":"Maurizio","family":"Miano","sequence":"first","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, 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implications","volume":"56","author":"Kallen","year":"2019","journal-title":"Semin. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.3389\/fimmu.2019.00316","article-title":"Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies","volume":"10","author":"Cifaldi","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ccell.2015.04.006","article-title":"SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition","volume":"27","author":"Kim","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.bbrc.2018.10.123","article-title":"Binding of SRSF4 to a novel enhancer modulates splicing of exon 6 of Fas pre-mRNA","volume":"506","author":"Jang","year":"2018","journal-title":"Biochem. Biophys. Res. 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Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"25441","DOI":"10.1038\/srep25441","article-title":"Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome","volume":"6","author":"Ravera","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1101\/gad.1934910","article-title":"A rational nomenclature for serine\/arginine-rich proteins plicing factors (SRproteins)","volume":"24","author":"Manley","year":"2010","journal-title":"Genes Dev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"724","DOI":"10.15252\/embj.201592862","article-title":"Mitochondria are required for pro-ageing features of the senescent phenotype","volume":"35","author":"Marques","year":"2016","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"473","DOI":"10.4161\/15384101.2014.991572","article-title":"mTOR coordinates protein synthesis, mitochondrial activity and proliferation","volume":"14","author":"Morita","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.201403129","article-title":"CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins","volume":"207","author":"Gao","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.3389\/fimmu.2022.935957","article-title":"Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity","volume":"13","author":"Signa","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101197","DOI":"10.1016\/j.beha.2020.101197","article-title":"Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9\/SAMD9L syndromes","volume":"33","author":"Sahoo","year":"2020","journal-title":"Best. Pract. Res. Clin. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s10875-018-0525-8","article-title":"Deficiency of Adenosine Deaminase 2 (DADA2): Up dates on the Phenotype, Genetics, Pathogenesis, and Treatment","volume":"38","author":"Meyts","year":"2018","journal-title":"J. Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1182\/blood-2014-06-580340","article-title":"GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia","volume":"125","author":"Ganapathi","year":"2015","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/bjh.17006","article-title":"Prevalence of germline GATA2 and SAMD9\/9L variants in paediatric haematological disorders with monosomy 7","volume":"191","author":"Yoshida","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/bjh.16098","article-title":"FAS-mediated apoptosis impairment in patients with ALPS\/ALPS-like phenotype carrying variants on CASP10 gene","volume":"187","author":"Miano","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gimeno-Valiente, F., L\u00f3pez-Rodas, G., Castillo, J., and Franco, L. (2022). Alternative Splicing, Epigenetic Modifications and Cancer: A Dangerous Triangle, or a Hopeful One?. Cancers, 14.","DOI":"10.3390\/cancers14030560"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.molcel.2017.08.013","article-title":"mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1","volume":"67","author":"Morita","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.cmet.2013.10.001","article-title":"mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation","volume":"18","author":"Morita","year":"2013","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s00018-017-2665-z","article-title":"Mesenchymal stem cells from preterm to term newborns undergo a significant switch from anaerobic glycolysis to the oxidative phosphorylation","volume":"75","author":"Ravera","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/j.bbabio.2012.02.033","article-title":"Bioenergetic role of mitochondrial fusion and fission","volume":"1817","author":"Westermann","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Bioenerg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.bbabio.2013.10.015","article-title":"The endoplasmic reticulum\u2013Mitochondria connection: Onetouch, multiple functions","volume":"1837","author":"Marchi","year":"2014","journal-title":"Biochim. Biophys. Acta (BBA) Bioenerg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1048746","DOI":"10.3389\/fonc.2022.1048746","article-title":"Acquired and hereditary bone marrow failure: A mitochondrial perspective","volume":"12","author":"Nasr","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/ncb3529","article-title":"The mitochondrial respiratory chain is essential for haematopoietic stem cell function","volume":"19","author":"Weinberg","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Grossi, A., Miano, M., Lanciotti, M., Fioredda, F., Guardo, D., Palmisani, E., Terranova, P., Santamaria, G., Caroli, F., and Caorsi, R. (2021). Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes, 12.","DOI":"10.3390\/genes12091299"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbabio.2004.09.004","article-title":"P\/O ratios of mitochondrial oxidative phosphorylation","volume":"1706","author":"Hinkle","year":"2005","journal-title":"Biochim. Biophys. Acta (BBA) Bioenerg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"70715","DOI":"10.18632\/oncotarget.12209","article-title":"Glutathione-mediated antioxidant response and aerobic metabolism: Two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma","volume":"7","author":"Colla","year":"2016","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2083\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:57:17Z","timestamp":1760104637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,8]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25042083"],"URL":"https:\/\/doi.org\/10.3390\/ijms25042083","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,2,8]]}}}