MicroRNAs are inappropriate for characterising hearing impairment in mitochondrial disorders

MicroRNAs are inappropriate for characterising hearing impairment in mitochondrial disorders Finsterer and Zarrouk-Mahjoub Orphanet Journal of Rare Diseases (2018) 13:87 https://doi.org/10.1186/s13023-018-0831-5 LETTER TO THE EDITOR Open Access MicroRNAs are inappropriate for characterising hearing impairment in mitochondrial disorders 1* 2 Josef Finsterer and Sinda Zarrouk-Mahjoub Keywords: Mitochondrial, Hereditary neuropathy, Phenotype, Genotype, Multisystem disease, Lactic acidosis Letter to the Editor why central causes of hypoacusis should be always We read with interest the review by Di Stadio et al. considered. Were central causes of hearing impair- about microRNAs (miRs) for the diagnostic work-up of ment excluded in all studies cited in the review hypoacusis in MELAS [1]. It was suspected that article? miR-34a, miR-29b, miR-299-3p, and miR-431 can be miRs are currently pushed and endeavoured as bio- useful as biomarkers for detecting and characterising markers or as etiologic or pathogenic factors of various inner ear involvement in MELAS [1]. We have the different disorders. However, miR levels are not only following comments and concerns. abnormal in genetic and inflammatory diseases or ageing We do not agree with the statement that “MELAS but also in malignancies (e.g. prostate cancer), metabolic shows the highest incidence of hearing loss” among conditions (e.g. diabetes), or neurodegenerative disorders mitochondrial disorders [1]. There is another specific (e.g. ALS) [6]. For example, miR-29b has been involved mitochondrial syndrome in which per definition in the etiology of prostate cancer [7], miR-34a promotes every patient presents with hearing impairment, cell cycle arrest and apoptosis and suppresses cell known as maternally inherited diabetes and deafness adhesion in osteosarcoma [8], miR-299-3p has been (MIDD) [2]. Additionally, hypoacusis is frequently shown to promote cell growth and to regulate G1/S found coenzyme-Q deficiency [3, 4]. transition in promyelocytic leukemia [9], and miR-431 We also do not agree with the statement that “coch- is known to regulate axon regeneration in mature lear conduction cannot be responsible for hearing impair- sensory neurons [10]. ment in MELAS” [1]. Mitochondria are present in nearly Additionally, miR levels may not only be influenced all cell types in high amounts, except for erythrocytes. by various pathologic conditions but also affected by Mitochondrial disorders (MIDs), including MELAS, may a number of drugs, such as statins [11]. Thus, we even manifest in the bone marrow, presenting as Pearson should be informed about the current medication of syndrome or other types of anemia [5] and, additionally, patients discussed in Dr. Di Stadio’sreview. It is also in sensory cells of the cochlea and mucosal cells of essential that we know how many of the discussed which the middle ear is fully lined with. patients had diabetes, a frequent manifestation of Hearing impairment in MIDs may not only be due MIDs, including MELAS. to a peripheral perception or conduction problem The authors also do not address the effect of hetero- but also due to a central conduction or processing plasmy on miR levels and on the variable phenotypes of defect. The organ most frequently affected in temporal bones and the cochlea. Also the influence of MELAS is the brain (epilepsy, stroke-like episodes, ageing on the miRs levels was not discussed. We should basal ganglia calcification, ataxia,atrophy,confusion, be informed about the age range of the included patients dementia, psychosis, leukoencephalopathy), this is and if miR levels were dependent on age. Overall, it remains speculative if miRs influence the * Correspondence: fifigs1@yahoo.de phenotype of patients carrying mutations in the Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria mtDNA or whether they reflect disease activity or Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Finsterer and Zarrouk-Mahjoub Orphanet Journal of Rare Diseases (2018) 13:87 Page 2 of 2 severity, including hearing function in MELAS. Due 8. Gang L, Qun L, Liu WD, Li YS, Xu YZ, Yuan DT. MicroRNA-34a promotes cell cycle arrest and apoptosis and suppresses cell adhesion by targeting DUSP1 to their multifactorial involvement, there is currently in osteosarcoma. Am J Transl Res. 2017;9:5388–99. no evidence for the usefulness of miRs as reliable 9. Wu SQ, Zhang LH, Huang HB, Li YP, Niu WY, Zhan R. miR-299-5p promotes biomarkers for disease activity, severity, and progres- cell growth and regulates G1/S transition by targeting p21Cip1/Waf1 in acute promyelocytic leukemia. Oncol Lett. 2016;12:741–7. sion, or whether they have a pathogenic effect in 10. Wu D, Murashov AK. MicroRNA-431 regulates axon regeneration in mature MELAS [12]. sensory neurons by targeting the Wnt antagonist Kremen1. Front Mol Neurosci. 2013;6:35. https://doi.org/10.3389/fnmol.2013.00035. Abbreviations 11. Zambrano T, Hirata RDC, Hirata MH, Cerda Á, Salazar LA. Statins differentially MELAS: Mitochondrial encephalopathy lactic acidosis and stroke-like epi- modulate microRNAs expression in peripheral cells of hyperlipidemic sodes; MID: Mitochondrial disorder; MIDD: Maternally inherited diabetes and subjects: a pilot study. Eur J Pharm Sci. 2018;117:55–61. deafness 12. Finsterer J, Zarrouk-Mahjoub S. Biomarkers for detecting mitochondrial disorders. J Clin Med. 2018;7(2) https://doi.org/10.3390/jcm7020016. Authors’ contributions Both authors contributed equally, JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments. Both authors read and approved the final manuscript. Ethics approval and consent to participate Not relevant Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1 2 Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria. Pasteur Institute of Tunis, University of Tunis El Manar and Genomics Platform, Tunis, Tunisia. Received: 6 March 2018 Accepted: 23 May 2018 References 1. Di Stadio A, Pegoraro V, Giaretta L, Dipietro L, Marozzo R, Angelini C. Hearing impairment in MELAS: new prospective in clinical use of microRNA, a systematic review. Orphanet J Rare Dis 2018;13(1):35. https://doi.org/10. 1186/s13023-018-0770-1. 2. Naing A, Kenchaiah M, Krishnan B, Mir F, Charnley A, Egan C, Bano G. Maternally inherited diabetes and deafness (MIDD): diagnosis and management. J Diabetes Complicat. 2014;28:542–6. 3. Park E, Ahn YH, Kang HG, Yoo KH, Won NH, Lee KB, Moon KC, Seong MW, Gwon TR, Park SS, Cheong HI. COQ6 mutations in children with steroid- resistant focal segmental glomerulosclerosis and sensorineural hearing loss. Am J Kidney Dis. 2017;70(1):139–44. 4. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Nürnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Müller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocaña C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nürnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011; 121(5):2013–24. 5. Finsterer J, Frank M. Haematological abnormalities in mitochondrial disorders. Singap Med J. 2015;56:412–9. 6. Si Y, CuiX,Crossman DK,Hao J, KazamelM,KwonY,KingPH. Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. Neurobiol Dis. 2018; https://doi.org/10. 1016/j.nbd.2018.02.009. 7. Ivanovic RF, Viana NI, Morais DR, Silva IA, Leite KR, Pontes-Junior J, Inoue G, Nahas WC, Srougi M, Reis ST. miR-29b enhances prostate cancer cell invasion independently of MMP-2 expression. Cancer Cell Int. 2018;18(18) https://doi.org/10.1186/s12935-018-0516-0. eCollection 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Orphanet Journal of Rare Diseases Springer Journals

MicroRNAs are inappropriate for characterising hearing impairment in mitochondrial disorders

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Medicine & Public Health; Medicine/Public Health, general; Pharmacology/Toxicology; Human Genetics
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Abstract

Finsterer and Zarrouk-Mahjoub Orphanet Journal of Rare Diseases (2018) 13:87 https://doi.org/10.1186/s13023-018-0831-5 LETTER TO THE EDITOR Open Access MicroRNAs are inappropriate for characterising hearing impairment in mitochondrial disorders 1* 2 Josef Finsterer and Sinda Zarrouk-Mahjoub Keywords: Mitochondrial, Hereditary neuropathy, Phenotype, Genotype, Multisystem disease, Lactic acidosis Letter to the Editor why central causes of hypoacusis should be always We read with interest the review by Di Stadio et al. considered. Were central causes of hearing impair- about microRNAs (miRs) for the diagnostic work-up of ment excluded in all studies cited in the review hypoacusis in MELAS [1]. It was suspected that article? miR-34a, miR-29b, miR-299-3p, and miR-431 can be miRs are currently pushed and endeavoured as bio- useful as biomarkers for detecting and characterising markers or as etiologic or pathogenic factors of various inner ear involvement in MELAS [1]. We have the different disorders. However, miR levels are not only following comments and concerns. abnormal in genetic and inflammatory diseases or ageing We do not agree with the statement that “MELAS but also in malignancies (e.g. prostate cancer), metabolic shows the highest incidence of hearing loss” among conditions (e.g. diabetes), or neurodegenerative disorders mitochondrial disorders [1]. There is another specific (e.g. ALS) [6]. For example, miR-29b has been involved mitochondrial syndrome in which per definition in the etiology of prostate cancer [7], miR-34a promotes every patient presents with hearing impairment, cell cycle arrest and apoptosis and suppresses cell known as maternally inherited diabetes and deafness adhesion in osteosarcoma [8], miR-299-3p has been (MIDD) [2]. Additionally, hypoacusis is frequently shown to promote cell growth and to regulate G1/S found coenzyme-Q deficiency [3, 4]. transition in promyelocytic leukemia [9], and miR-431 We also do not agree with the statement that “coch- is known to regulate axon regeneration in mature lear conduction cannot be responsible for hearing impair- sensory neurons [10]. ment in MELAS” [1]. Mitochondria are present in nearly Additionally, miR levels may not only be influenced all cell types in high amounts, except for erythrocytes. by various pathologic conditions but also affected by Mitochondrial disorders (MIDs), including MELAS, may a number of drugs, such as statins [11]. Thus, we even manifest in the bone marrow, presenting as Pearson should be informed about the current medication of syndrome or other types of anemia [5] and, additionally, patients discussed in Dr. Di Stadio’sreview. It is also in sensory cells of the cochlea and mucosal cells of essential that we know how many of the discussed which the middle ear is fully lined with. patients had diabetes, a frequent manifestation of Hearing impairment in MIDs may not only be due MIDs, including MELAS. to a peripheral perception or conduction problem The authors also do not address the effect of hetero- but also due to a central conduction or processing plasmy on miR levels and on the variable phenotypes of defect. The organ most frequently affected in temporal bones and the cochlea. Also the influence of MELAS is the brain (epilepsy, stroke-like episodes, ageing on the miRs levels was not discussed. We should basal ganglia calcification, ataxia,atrophy,confusion, be informed about the age range of the included patients dementia, psychosis, leukoencephalopathy), this is and if miR levels were dependent on age. Overall, it remains speculative if miRs influence the * Correspondence: fifigs1@yahoo.de phenotype of patients carrying mutations in the Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria mtDNA or whether they reflect disease activity or Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Finsterer and Zarrouk-Mahjoub Orphanet Journal of Rare Diseases (2018) 13:87 Page 2 of 2 severity, including hearing function in MELAS. Due 8. Gang L, Qun L, Liu WD, Li YS, Xu YZ, Yuan DT. MicroRNA-34a promotes cell cycle arrest and apoptosis and suppresses cell adhesion by targeting DUSP1 to their multifactorial involvement, there is currently in osteosarcoma. Am J Transl Res. 2017;9:5388–99. no evidence for the usefulness of miRs as reliable 9. Wu SQ, Zhang LH, Huang HB, Li YP, Niu WY, Zhan R. miR-299-5p promotes biomarkers for disease activity, severity, and progres- cell growth and regulates G1/S transition by targeting p21Cip1/Waf1 in acute promyelocytic leukemia. Oncol Lett. 2016;12:741–7. sion, or whether they have a pathogenic effect in 10. Wu D, Murashov AK. MicroRNA-431 regulates axon regeneration in mature MELAS [12]. sensory neurons by targeting the Wnt antagonist Kremen1. Front Mol Neurosci. 2013;6:35. https://doi.org/10.3389/fnmol.2013.00035. Abbreviations 11. Zambrano T, Hirata RDC, Hirata MH, Cerda Á, Salazar LA. Statins differentially MELAS: Mitochondrial encephalopathy lactic acidosis and stroke-like epi- modulate microRNAs expression in peripheral cells of hyperlipidemic sodes; MID: Mitochondrial disorder; MIDD: Maternally inherited diabetes and subjects: a pilot study. Eur J Pharm Sci. 2018;117:55–61. deafness 12. Finsterer J, Zarrouk-Mahjoub S. Biomarkers for detecting mitochondrial disorders. J Clin Med. 2018;7(2) https://doi.org/10.3390/jcm7020016. Authors’ contributions Both authors contributed equally, JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments. Both authors read and approved the final manuscript. Ethics approval and consent to participate Not relevant Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1 2 Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria. Pasteur Institute of Tunis, University of Tunis El Manar and Genomics Platform, Tunis, Tunisia. Received: 6 March 2018 Accepted: 23 May 2018 References 1. Di Stadio A, Pegoraro V, Giaretta L, Dipietro L, Marozzo R, Angelini C. Hearing impairment in MELAS: new prospective in clinical use of microRNA, a systematic review. Orphanet J Rare Dis 2018;13(1):35. https://doi.org/10. 1186/s13023-018-0770-1. 2. Naing A, Kenchaiah M, Krishnan B, Mir F, Charnley A, Egan C, Bano G. Maternally inherited diabetes and deafness (MIDD): diagnosis and management. J Diabetes Complicat. 2014;28:542–6. 3. Park E, Ahn YH, Kang HG, Yoo KH, Won NH, Lee KB, Moon KC, Seong MW, Gwon TR, Park SS, Cheong HI. COQ6 mutations in children with steroid- resistant focal segmental glomerulosclerosis and sensorineural hearing loss. Am J Kidney Dis. 2017;70(1):139–44. 4. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rötig A, Nürnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Müller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocaña C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nürnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011; 121(5):2013–24. 5. Finsterer J, Frank M. Haematological abnormalities in mitochondrial disorders. Singap Med J. 2015;56:412–9. 6. Si Y, CuiX,Crossman DK,Hao J, KazamelM,KwonY,KingPH. Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. Neurobiol Dis. 2018; https://doi.org/10. 1016/j.nbd.2018.02.009. 7. Ivanovic RF, Viana NI, Morais DR, Silva IA, Leite KR, Pontes-Junior J, Inoue G, Nahas WC, Srougi M, Reis ST. miR-29b enhances prostate cancer cell invasion independently of MMP-2 expression. Cancer Cell Int. 2018;18(18) https://doi.org/10.1186/s12935-018-0516-0. eCollection 2018

Journal

Orphanet Journal of Rare DiseasesSpringer Journals

Published: May 31, 2018

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