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HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES

Yıl 2024, Cilt: 87 Sayı: 1, 1 - 10, 29.01.2024

Çağrı Güleç Asuman Gedikbaşı Gökçen Şahin Güven Toksoy Altuğ Duramaz Zehra Oya Uyguner

https://doi.org/10.26650/IUITFD.1394708

Öz

Objective: Mitochondrial heteroplasmy, a recognized trait in eukaryotic cells, plays a pivotal role in complex disorders like mitochondrial diseases. High-throughput sequencing has improved precision in detecting low-level heteroplasmy and can identify ultra-low-level variants (<1%) associated with heteroplasmy attributes. We aimed to investigate potential genetic and demographic factors associated with heteroplasmy levels in mitochondrial variants by analyzing both blood and muscle tissues in individuals, regardless of their phenotypes.
Material and Methods: High-throughput sequencing was conducted on the mitochondrial genomes of 10 individuals, with an equal gender distribution. Variants with heteroplasmy ratios both ranging from 5% to 95% and out of this range were used for statistical analysis.
Result: A total of 194 heteroplasmic variants were identified, of which 13 displayed lower heteroplasmy ratios in both blood and skeletal muscle samples from females, while the mitochondrial control region (D-Loop) exhibited higher ratios.
Conclusion: The study findings confirm the correlation between the m.10398A>G variant and mitochondrial heteroplasmy levels, consistent with prior research. Additionally, we identified the m.1811A>G variant in MT-RNR2 and the m.12308A>G variant in MT-TL2, both associated with higher heteroplasmy. Conversely, the m.582T>C variant in MT-TF, m.3260A>G in MT-TL1, m.3302A>G in MT-TL1, m.4409T>C in MT-TM, and m.4267A>G in MT-TI were linked to lower heteroplasmy, all involving transition-type alterations. Furthermore, our study hinted at a potential age-related threshold for variant accumulation in the control region. Future studies, involving larger cohorts and advanced expression analysis methods, will further contribute to the validation and enhancement of these findings.

Anahtar Kelimeler

Mitochondrial heteroplasmy MT-TL1 MT-TL2 MTRNR2 MT-TM MT-TI MT-TF

Etik Beyan

The study has ethical approval from the Istanbul Faculty of Medicine Ethics Council at Istanbul University (Approval numbers: 1626/2018 and 872/2018.

Destekleyen Kurum

This study was supported by the Scientific Research Projects Coordination Unit of Istanbul University, Project No. TYL-2019-33447 and TDK-2018-32544.

Teşekkür

The authors extend their gratitude to the donors for their invaluable participation in this study.

Kaynakça

  • 1. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature 1981;290(5806):457-65. [CrossRef] google scholar
  • 2. Attardi G, Schatz G. Biogenesis of mitochondria. Annu Rev Cell Biol 1988;4:289-333. [CrossRef] google scholar
  • 3. Clayton DA. Transcription and replication of mitochondrial DNA. Hum Reprod 2000;15(Suppl 2):11-7. [CrossRef] google scholar
  • 4. Yasukawa T, Reyes A, Cluett TJ, Yang MY, Bowmaker M, Jacobs HT, et al. Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strand. EMBO J 2006;25(22):5358-71. [CrossRef] google scholar
  • 5. Bonawitz ND, Clayton DA, Shadel GS. Initiation and beyond: multiple functions ofthe human mitochondrial transcription machinery. Mol Cell 2006;24(6):813-25. [CrossRef] google scholar
  • 6. Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet 2015;16(9):530-42. [CrossRef] google scholar
  • 7. Frezza C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus 2017;7(2):20160100. [CrossRef] google scholar
  • 8. Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 1997;94(2):514-9. [CrossRef] google scholar
  • 9. Li M, Schonberg A, Schaefer M, Schroeder R, Nasidze I, Stoneking M. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am J Hum Genet 2010;87(2):237-49. [CrossRef] google scholar
  • 10. Payne BA, Wilson IJ, Yu-Wai-Man P, Coxhead J, Deehan D, Horvath R, et al. Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 2013;22(2):384-90. [CrossRef] google scholar
  • 11. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 1999;23(2):147. [CrossRef] google scholar
  • 12. Laaksonen J, Mishra PP, Seppala I, Lyytikainen LP, Raitoharju E, Mononen N, et al. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts. Sci Rep 2021;11(1):611. [CrossRef] google scholar
  • 13. Stoneking M. Hypervariable sites in the mtDNA control region are mutational hotspots. Am J Hum Genet 2000;67(4):1029-32. [CrossRef] google scholar
  • 14. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 1992;2(4):324-9. [CrossRef] google scholar
  • 15. Ye K, Lu J, Ma F, Keinan A, Gu Z. Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proc Natl Acad Sci U S A 2014;111(29):10654-9. [CrossRef] google scholar
  • 16. Diroma MA, Calabrese C, Simone D, Santorsola M, Calabrese FM, Gasparre G, et al. Extraction and annotation of human mitochondrial genomes from 1000 Genomes Whole Exome Sequencing data. BMC Genomics 2014;15(Suppl 3):S2. [CrossRef] google scholar
  • 17. Mullin NK, Voigt AP, Flamme-Wiese MJ, Liu X, Riker MJ, Varzavand K, et al. Multimodal single-cell analysis of nonrandom heteroplasmy distribution in human retinal mitochondrial disease. JCI Insight 2023;8(14):e165937. [CrossRef] google scholar
  • 18. Imasawa T, Kitamura H, Kawaguchi T, Yatsuka Y, Okazaki Y, Murayama K. Changes in histopathology and heteroplasmy rates over 8 years and effectiveness of taurine supplementation in a patient with mitochondrial nephropathy caused by MT-TL1 mutation: A case report. Heliyon 2023;9(4):e14923. [CrossRef] google scholar
  • 19. Leititis JU, Burghard R, Gordjani N, Wildberg A, Seyberth HW, Brandis M. Effect of a modified fluid therapy on renal function during indomethacin therapy for persistent ductus arteriosus. Acta Paediatr Scand 1987;76(5):789-94. [CrossRef] google scholar
  • 20. Trinh J, Hicks AA, Konig IR, Delcambre S, Luth T, Schaake S, et al. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease. Brain 2023;146(7):2753-65. [CrossRef] google scholar
  • 21. He Y, Wu J, Dressman DC, Iacobuzio-Donahue C, Markowitz SD, Velculescu VE, et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 2010;464(7288):610-4. [CrossRef] google scholar
  • 22. Larman TC, DePalma SR, Hadjipanayis AG, Cancer Genome Atlas Research N, Protopopov A, Zhang J, et al. Spectrum of somatic mitochondrial mutations in five cancers Proc Natl Acad Sci U S A. 2012;109(35):14087-91. [CrossRef] google scholar
  • 23. Avital G, Buchshtav M, Zhidkov I, Tuval Feder J, Dadon S, Rubin E, et al. Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins. Hum Mol Genet 2012;21(19):4214-24. [CrossRef] google scholar
  • 24. Lorca R, Aparicio A, Gomez J, Alvarez-Velasco R, Pascual I, Avanzas P, et al. Mitochondrial Heteroplasmy as a Marker for Premature Coronary Artery Disease: Analysis of the Poly-C Tract of the Control Region Sequence. J Clin Med 2023;12(6):2133. [CrossRef] google scholar
  • 25. Wang Y, Guo X, Hong X, Wang G, Pearson C, Zuckerman B, et al. Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism. Nat Commun 2022;13(1):3790. [CrossRef] google scholar
  • 26. Legati A, Ghezzi D, Viscomi C. Mitochondrial DNA Sequencing and Heteroplasmy Quantification by Next Generation Sequencing. Methods Mol Biol 2023;2615:381-95. [CrossRef] google scholar
  • 27. Kaneva K, Merkurjev D, Ostrow D, Ryutov A, Triska P, Stachelek K, et al. Detection of mitochondrial DNA variants at low level heteroplasmy in pediatric CNS and extra-CNS solid tumors with three different enrichment methods. Mitochondrion 2020;51:97-103. [CrossRef] google scholar
  • 28. Kennedy SR, Salk JJ, Schmitt MW, Loeb LA. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 2013;9(9):e1003794. [CrossRef] google scholar
  • 29. Samuels DC, Li C, Li B, Song Z, Torstenson E, Boyd Clay H, et al. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet 2013;9(11):e1003929. [CrossRef] google scholar
  • 30. Frederiksen AL, Andersen PH, Kyvik KO, Jeppesen TD, Vissing J, Schwartz M. Tissue specific distribution of the 3243A->G mtDNA mutation. J Med Genet 2006;43(8):671-7. [CrossRef] google scholar
  • 31. Grady JP, Pickett SJ, Ng YS, Alston CL, Blakely EL, Hardy SA, et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med 2018;10(6):e8262. [CrossRef] google scholar
  • 32. Lee HY, Chung U, Park MJ, Yoo JE, Han GR, Shin KJ. Differential distribution of human mitochondrial DNA in somatic tissues and hairs. Ann Hum Genet 2006;70(Pt 1):59-65. [CrossRef] google scholar
  • 33. Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG, Chinnery PF, et al. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 2023;620(7975):839-48. [CrossRef] google scholar
  • 34. Nandakumar P, Tian C, O’Connell J, andMe Research T, Hinds D, Paterson AD, et al. Nuclear genome-wide associations with mitochondrial heteroplasmy. Sci Adv 2021;7(12):eabe7520. [CrossRef] google scholar
  • 35. Smullen M, Olson MN, Murray LF, Suresh M, Yan G, Dawes P, et al. Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G. Sci Rep 2023;13(1):10405. [CrossRef] google scholar
  • 36. Rovcanin B, Jancic J, Samardzic J, Rovcanin M, Nikolic B, Ivancevic N, et al. In silico model of mtDNA mutations effect on secondary and 3D structure of mitochondrial rRNA and tRNA in Leber’s hereditary optic neuropathy. Exp Eye Res 2020;201:108277. [CrossRef] google scholar

İNSAN KAN VE İSKELET KASI ÖRNEKLERİNDE HETEROPLAZMİYLE İLİŞKİLİ MİTOKONDRİYAL DNA VARYANTLARI

Yıl 2024, Cilt: 87 Sayı: 1, 1 - 10, 29.01.2024

Çağrı Güleç Asuman Gedikbaşı Gökçen Şahin Güven Toksoy Altuğ Duramaz Zehra Oya Uyguner

https://doi.org/10.26650/IUITFD.1394708

Öz

Amaç: Ökaryotik hücrelerin tanımlanmış bir özelliği olan mitokondriyel heteroplazmi, mitokondriyel hastalıkların fenotipik çeşitliliğinde önemli bir rol oynar. Düşük düzeydeki heteroplazminin tespitindeki hassasiyeti artıran yeni nesil dizileme (YND) teknolojisi, heteroplazmi özellikleri ile ilişkili ultra-düşük düzeydeki (%<1) varyantları saptayabilmektedir. Çalışmamız, fenotiplerine bakılmaksızın, bireylerdeki mitokondriyel varyantların heteroplazmi düzeyleri ile ilişkilendirilebilecek potansiyel genetik ve demografik faktörleri incelemeyi amaçlandı.
Gereç ve Yöntem: Cinsiyet dağılımı eşit olan 10 bireyin mitokondriyel genomları üzerinde, yüksek-çıktılı yeni nesil dizileme yöntemi uygulandı. Heteroplazmi oranları %5 ile %95 arasında değişen ve bu aralığın dışında kalan varyantlar, istatistiksel analizler için kullanıldı.
Bulgular: Toplamda 194 heteroplazmik varyant tanımlandı, bunlardan 13'ü dişi bireylerin hem kan hem de iskelet kası örneklerinde daha düşük heteroplazmi oranları sergilerken, mitokondrial kontrol bölgesi (D-ilmiği) daha yüksek oranlara sahipti.
Sonuç: Çalışma bulguları, önceki araştırmalarla uyumlu olarak m.10398A>G varyantı ile mitokondriyel heteroplazmi düzeyleri arasındaki korelasyonu doğruladı. Ayrıca, MT-RNR2 genindeki m.1811A>G varyantının ve MT-TL2 genindeki m.12308A>G varyantının da yüksek heteroplazmi ile ilişkili olduğu gösterildi. Bunun yanı sıra, hepsi tranzisyon tipinde olan, MT-TF genindeki m.582T>C, MT-TL1 genindeki m.3260A>G, MT-TL1 genindeki m.3302A>G, MT-TM genindeki m.4409T>C ve MT-TI genindeki m.4267A>G varyantlarının ise düşük heteroplazmi oranı ile ilişkili olduğu bulundu. Çalışmamız ayrıca, kontrol bölgesindeki varyant birikimi için potansiyel bir yaş sınır eşiği olabileceğini de işaret etmiştir. Gelecekte, daha büyük örnek sayısı ve gelişmiş analiz yöntemlerinin kullanılacağı çalışmalar, bu bulguların doğrulanması ve geliştirilmesine katkı sağlayacaktır.

Anahtar Kelimeler

Mitokondriyel heteroplazmi MT-TL1 MTTL2 MT-RNR2 MT-TM MT-TI MT-TF

Kaynakça

  • 1. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature 1981;290(5806):457-65. [CrossRef] google scholar
  • 2. Attardi G, Schatz G. Biogenesis of mitochondria. Annu Rev Cell Biol 1988;4:289-333. [CrossRef] google scholar
  • 3. Clayton DA. Transcription and replication of mitochondrial DNA. Hum Reprod 2000;15(Suppl 2):11-7. [CrossRef] google scholar
  • 4. Yasukawa T, Reyes A, Cluett TJ, Yang MY, Bowmaker M, Jacobs HT, et al. Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strand. EMBO J 2006;25(22):5358-71. [CrossRef] google scholar
  • 5. Bonawitz ND, Clayton DA, Shadel GS. Initiation and beyond: multiple functions ofthe human mitochondrial transcription machinery. Mol Cell 2006;24(6):813-25. [CrossRef] google scholar
  • 6. Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet 2015;16(9):530-42. [CrossRef] google scholar
  • 7. Frezza C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus 2017;7(2):20160100. [CrossRef] google scholar
  • 8. Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 1997;94(2):514-9. [CrossRef] google scholar
  • 9. Li M, Schonberg A, Schaefer M, Schroeder R, Nasidze I, Stoneking M. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am J Hum Genet 2010;87(2):237-49. [CrossRef] google scholar
  • 10. Payne BA, Wilson IJ, Yu-Wai-Man P, Coxhead J, Deehan D, Horvath R, et al. Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 2013;22(2):384-90. [CrossRef] google scholar
  • 11. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 1999;23(2):147. [CrossRef] google scholar
  • 12. Laaksonen J, Mishra PP, Seppala I, Lyytikainen LP, Raitoharju E, Mononen N, et al. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts. Sci Rep 2021;11(1):611. [CrossRef] google scholar
  • 13. Stoneking M. Hypervariable sites in the mtDNA control region are mutational hotspots. Am J Hum Genet 2000;67(4):1029-32. [CrossRef] google scholar
  • 14. Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 1992;2(4):324-9. [CrossRef] google scholar
  • 15. Ye K, Lu J, Ma F, Keinan A, Gu Z. Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proc Natl Acad Sci U S A 2014;111(29):10654-9. [CrossRef] google scholar
  • 16. Diroma MA, Calabrese C, Simone D, Santorsola M, Calabrese FM, Gasparre G, et al. Extraction and annotation of human mitochondrial genomes from 1000 Genomes Whole Exome Sequencing data. BMC Genomics 2014;15(Suppl 3):S2. [CrossRef] google scholar
  • 17. Mullin NK, Voigt AP, Flamme-Wiese MJ, Liu X, Riker MJ, Varzavand K, et al. Multimodal single-cell analysis of nonrandom heteroplasmy distribution in human retinal mitochondrial disease. JCI Insight 2023;8(14):e165937. [CrossRef] google scholar
  • 18. Imasawa T, Kitamura H, Kawaguchi T, Yatsuka Y, Okazaki Y, Murayama K. Changes in histopathology and heteroplasmy rates over 8 years and effectiveness of taurine supplementation in a patient with mitochondrial nephropathy caused by MT-TL1 mutation: A case report. Heliyon 2023;9(4):e14923. [CrossRef] google scholar
  • 19. Leititis JU, Burghard R, Gordjani N, Wildberg A, Seyberth HW, Brandis M. Effect of a modified fluid therapy on renal function during indomethacin therapy for persistent ductus arteriosus. Acta Paediatr Scand 1987;76(5):789-94. [CrossRef] google scholar
  • 20. Trinh J, Hicks AA, Konig IR, Delcambre S, Luth T, Schaake S, et al. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease. Brain 2023;146(7):2753-65. [CrossRef] google scholar
  • 21. He Y, Wu J, Dressman DC, Iacobuzio-Donahue C, Markowitz SD, Velculescu VE, et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 2010;464(7288):610-4. [CrossRef] google scholar
  • 22. Larman TC, DePalma SR, Hadjipanayis AG, Cancer Genome Atlas Research N, Protopopov A, Zhang J, et al. Spectrum of somatic mitochondrial mutations in five cancers Proc Natl Acad Sci U S A. 2012;109(35):14087-91. [CrossRef] google scholar
  • 23. Avital G, Buchshtav M, Zhidkov I, Tuval Feder J, Dadon S, Rubin E, et al. Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins. Hum Mol Genet 2012;21(19):4214-24. [CrossRef] google scholar
  • 24. Lorca R, Aparicio A, Gomez J, Alvarez-Velasco R, Pascual I, Avanzas P, et al. Mitochondrial Heteroplasmy as a Marker for Premature Coronary Artery Disease: Analysis of the Poly-C Tract of the Control Region Sequence. J Clin Med 2023;12(6):2133. [CrossRef] google scholar
  • 25. Wang Y, Guo X, Hong X, Wang G, Pearson C, Zuckerman B, et al. Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism. Nat Commun 2022;13(1):3790. [CrossRef] google scholar
  • 26. Legati A, Ghezzi D, Viscomi C. Mitochondrial DNA Sequencing and Heteroplasmy Quantification by Next Generation Sequencing. Methods Mol Biol 2023;2615:381-95. [CrossRef] google scholar
  • 27. Kaneva K, Merkurjev D, Ostrow D, Ryutov A, Triska P, Stachelek K, et al. Detection of mitochondrial DNA variants at low level heteroplasmy in pediatric CNS and extra-CNS solid tumors with three different enrichment methods. Mitochondrion 2020;51:97-103. [CrossRef] google scholar
  • 28. Kennedy SR, Salk JJ, Schmitt MW, Loeb LA. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 2013;9(9):e1003794. [CrossRef] google scholar
  • 29. Samuels DC, Li C, Li B, Song Z, Torstenson E, Boyd Clay H, et al. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet 2013;9(11):e1003929. [CrossRef] google scholar
  • 30. Frederiksen AL, Andersen PH, Kyvik KO, Jeppesen TD, Vissing J, Schwartz M. Tissue specific distribution of the 3243A->G mtDNA mutation. J Med Genet 2006;43(8):671-7. [CrossRef] google scholar
  • 31. Grady JP, Pickett SJ, Ng YS, Alston CL, Blakely EL, Hardy SA, et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med 2018;10(6):e8262. [CrossRef] google scholar
  • 32. Lee HY, Chung U, Park MJ, Yoo JE, Han GR, Shin KJ. Differential distribution of human mitochondrial DNA in somatic tissues and hairs. Ann Hum Genet 2006;70(Pt 1):59-65. [CrossRef] google scholar
  • 33. Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG, Chinnery PF, et al. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 2023;620(7975):839-48. [CrossRef] google scholar
  • 34. Nandakumar P, Tian C, O’Connell J, andMe Research T, Hinds D, Paterson AD, et al. Nuclear genome-wide associations with mitochondrial heteroplasmy. Sci Adv 2021;7(12):eabe7520. [CrossRef] google scholar
  • 35. Smullen M, Olson MN, Murray LF, Suresh M, Yan G, Dawes P, et al. Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G. Sci Rep 2023;13(1):10405. [CrossRef] google scholar
  • 36. Rovcanin B, Jancic J, Samardzic J, Rovcanin M, Nikolic B, Ivancevic N, et al. In silico model of mtDNA mutations effect on secondary and 3D structure of mitochondrial rRNA and tRNA in Leber’s hereditary optic neuropathy. Exp Eye Res 2020;201:108277. [CrossRef] google scholar
Toplam 36 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Hizmetleri ve Sistemleri (Diğer)
Bölüm ARAŞTIRMA
Yazarlar

Çağrı Güleç 0000-0002-1256-9574

Asuman Gedikbaşı 0000-0001-7121-6077

Gökçen Şahin 0000-0002-1372-9234

Güven Toksoy 0000-0002-8103-9980

Altuğ Duramaz 0000-0002-5012-2079

Zehra Oya Uyguner 0000-0002-2035-4338

Yayımlanma Tarihi 29 Ocak 2024
Gönderilme Tarihi 23 Kasım 2023
Kabul Tarihi 25 Aralık 2023
Yayımlandığı Sayı Yıl 2024 Cilt: 87 Sayı: 1

Kaynak Göster

APA Güleç, Ç., Gedikbaşı, A., Şahin, G., Toksoy, G., vd. (2024). HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES. Journal of Istanbul Faculty of Medicine, 87(1), 1-10. https://doi.org/10.26650/IUITFD.1394708
AMA Güleç Ç, Gedikbaşı A, Şahin G, Toksoy G, Duramaz A, Uyguner ZO. HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES. İst Tıp Fak Derg. Ocak 2024;87(1):1-10. doi:10.26650/IUITFD.1394708
Chicago Güleç, Çağrı, Asuman Gedikbaşı, Gökçen Şahin, Güven Toksoy, Altuğ Duramaz, ve Zehra Oya Uyguner. “HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES”. Journal of Istanbul Faculty of Medicine 87, sy. 1 (Ocak 2024): 1-10. https://doi.org/10.26650/IUITFD.1394708.
EndNote Güleç Ç, Gedikbaşı A, Şahin G, Toksoy G, Duramaz A, Uyguner ZO (01 Ocak 2024) HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES. Journal of Istanbul Faculty of Medicine 87 1 1–10.
IEEE Ç. Güleç, A. Gedikbaşı, G. Şahin, G. Toksoy, A. Duramaz, ve Z. O. Uyguner, “HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES”, İst Tıp Fak Derg, c. 87, sy. 1, ss. 1–10, 2024, doi: 10.26650/IUITFD.1394708.
ISNAD Güleç, Çağrı vd. “HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES”. Journal of Istanbul Faculty of Medicine 87/1 (Ocak 2024), 1-10. https://doi.org/10.26650/IUITFD.1394708.
JAMA Güleç Ç, Gedikbaşı A, Şahin G, Toksoy G, Duramaz A, Uyguner ZO. HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES. İst Tıp Fak Derg. 2024;87:1–10.
MLA Güleç, Çağrı vd. “HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES”. Journal of Istanbul Faculty of Medicine, c. 87, sy. 1, 2024, ss. 1-10, doi:10.26650/IUITFD.1394708.
Vancouver Güleç Ç, Gedikbaşı A, Şahin G, Toksoy G, Duramaz A, Uyguner ZO. HETEROPLASMY-ASSOCIATED MITOCHONDRIAL DNA VARIANTS IN HUMAN BLOOD AND SKELETAL MUSCLE SAMPLES. İst Tıp Fak Derg. 2024;87(1):1-10.
 Kapak Resmi İndir

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