Heteroplasmic mutation of m.3243A>G mitochondrial DNA in the Yakut family with MELAS syndrome: connection with phenotypic manifestations
R. N. Zakharova,
D. G. Tikhonov,
M. V. Golubenko,
T. M. Sivtseva,
S. I. Semenov,
A. A. Tappakhov,
T. Ya. Nikolaeva,
T. M. Klimova,
V. L. Osakovsky,
S. A. Fedorova https://doi.org/10.25789/YMJ.2024.85.30
Abstract
For the first time, the diagnosis of MELAS syndrome in a Yakut family was genetically verified using mitochondrial genome sequencing. The substitution of adenine for guanine at position 3243 (m.3243A>G) in the tRNALeu(UUR) gene (MT-TL1) was confirmed. The level of the mutant allele (heteroplasmia) in the patient was 38.5%, while in the mother only 9.8%, which is ex- plained by the selection of rapidly dividing blood cells with a low level of mutant alleles during life. It has been shown that the phenomenon of mtDNA heteroplasmy forms a significant clinical heterogeneity in the manifestation of the disease and demonstrates the complexity of diagnosing subclinical forms of MELAS.
Supporting agencies: The study was funded by the Ministry of Education and Science of the Russian Federation (project FSRG-2023-0003 “Genetic characteristics of the population of the north-east of Russia: reconstruc- tion of genetic history, mechanisms of adaptation and aging, age-related and hereditary diseases”).
About the Authors
R. N. Zakharova
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
ZAKHAROVA Raisa Nikolaevna – Ph.D., Leading Researcher, Research Center
D. G. Tikhonov
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
TIKHONOV Dmitry Gavrilyevich – MD, Chief Researcher, Research Center
M. V. Golubenko
Tomsk National Research Medical Center
Russian Federation
Russian Federation
GOLUBENKO Maria Vladimirovna – Ph.D., senior researcher laboratories of population genetics of the Research Institute of Medical Genetics
T. M. Sivtseva
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
SIVTSEVA Tatyana Mikhailovna – Ph.D., Leading Researcher, Research Center
S. I. Semenov
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
SEMENOV Sergey Innokentievich – MD, Leading Researcher, Research Center
A. A. Tappakhov
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
TAPPAKHOV Aleksey Alekseevich – Ph.D., Associate Professor, Department of Neurology and Psychiatry
T. Ya. Nikolaeva
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
NIKOLAEVA Tatyana Yakovlevna – MD, head of the Department of Neurology and Psychiatry
T. M. Klimova
Medical Institute of the M.K. Ammosov North-Eastern Federal University; Yakutsk Science Center for Complex Medical Problems
Russian Federation
Russian Federation
KLIMOVA Tatyana Mikhailovna – Ph.D., Associate Professor of the Department of Pharmacology and Pharmacy, Senior Researcher of the Research Center; Senior Researcher, Department of Epidemiology of Chronic Noncommunicable Diseases
V. L. Osakovsky
Medical Institute of the M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
OSAKOVSKY Vladimir Leonidovich – Ph.D., Chief Researcher, Research Center
S. A. Fedorova
Institute of Natural Sciences, M.K. Ammosov North-Eastern Federal University
Russian Federation
Russian Federation
FEDOROVA Sardana Arkadievna – Dr. Biol. Sci., Chief Researcher, Research Laboratory of Molecular Biology
References
1. Umyarova D.Sh. [et al.]. MELAS-sindrom kak neobychnaya prichina gipoparatireoza: klinicheskoe nabludenie [MELAS syndrome as an unusual cause of hypoparathyroidism: a clinical observation]. Osteoporoz I osteopatii [Osteoporosis and osteopathy. 2018; 3:30-35 (In Russ.).]. DOI 10.14341/osteo10094.
2. Kharlamov D.A. [et al.] Nevrologicheskiye narusheniya pri mitokhondrialnoy encephalomiopatii – laktatatsidoze s insultopodobnymi epizodami (syndrome MELAS) [Neurological disorders in mitochondrial encephalomyopathy – lactate acidosis with stroke-like episodes (MELAS syndrome)]. Ros vestn perinatol and pediatrics [Russian Bulletin of Perinatology and Pediatrics. 2012; 4(2): 44-50 (In Russ.).].
3. Ulyanova O.V., Kutashov V.A. MELAS: osobennosti diagnostiki, techeniya zabolevaniya I lecheniya (klinicheskiy sluchay) [MELAS syndrome: features of diagnosis, course of the disease and treatment (clinical case). Saratov Scientific Medical Journal. 2021; 1:155-159 (In Russ.).].
4. Dzhemilova L.U. [et al.] Analysis of mitochondrial 12S rRNA and tRNASer(UCN) genes in patients with nonsyndromic sensorineural hearing loss from various regions of Russia. Russian Journal of Genetics. 2009; 45 (7): 861-869. DOI 10.1134/S1022795409070151.
5. Fedorova S.A. [et al.]. Autosomal and uniparental portraits of the native populations of Sakha (Yakutia): implications for the peopling of Northeast Eurasia. BMC evolutionary biology. 2013; 13:127. doi:10.1186/1471-2148-13-127
6. Seiler F. [et al.] Bilateral deafness, diabetes, and different types of cardiomyopathy in family members with m.3243A > g mutation: a case report. Eur Heart J Case Rep. 2023;7(2):ytad073. doi: 10.1093/ehjcr/ytad073.
7. Rahman S. [et al.]. Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet. 2001; 68(1): 238-40. doi: 10.1086/316930.
8. Goto Y., Nonaka I., Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990; 348(6302): 651-3. doi: 10.1038/348651a0.
9. Askapuli A., [et al.] Kazak mitochondrial genomes provide insights into the human population history of Central Eurasia. PLoS One. 2022; 17(11): e0277771. doi: 10.1371/journal. pone.0277771.
10. Kwak SH, Park KS. Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus. Front Biosci (Landmark Ed). 2016 Jun 1;21(6):1151-67. doi: 10.2741/4447.
11. Alves C, [et al.] MELAS: Phenotype Classification into Classic-versus-Atypical Presentations. American Journal of Neuroradiology. 2023; 44(5): 602–610. https://doi.org/10.3174/ajnr. A7837
12. Ng YS, [et al.]. //Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. 2021 Jul;20(7):573-584. doi: 10.1016/ S1474-4422(21)00098-3.
13. Peng MS, [et al.]. Mitochondrial genomes uncover the maternal history of the Pamir populations. European Journal of Human Genetics. 2018: 26: 124–136. https://doi.org/10.1038/ s41431-017-0028-8
14. Derenko M. [et al.] Origin and Post-Glacial Dispersal of Mitochondrial DNA Haplogroups C and D in Northern Asia. PLoS One. 2010; 5(12): e15214. doi: 10.1371/journal.pone.0015214
15. Thajeb P, [et al.] Phenotypic heterogeneity in a Chinese family with mitochondrial disease and A3243G mutation of mitochondrial DNA. Zhonghua Yi Xue kZa Zhi (Taipei). – 2000; 63(1):71-6.
16. Picard M, [et al.]. Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci U S A. 2014; 111(38):E4033-42. doi: 10.1073/ pnas.1414028111.
17. Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat. 1994;3(3):243-7. doi: 10.1002/ humu.1380030311.
Review
For citations:
Zakharova R.N., Tikhonov D.G., Golubenko M.V., Sivtseva T.M., Semenov S.I., Tappakhov A.A., Nikolaeva T.Ya., Klimova T.M., Osakovsky V.L., Fedorova S.A. Heteroplasmic mutation of m.3243A>G mitochondrial DNA in the Yakut family with MELAS syndrome: connection with phenotypic manifestations. Yakut Medical Journal. 2024;(1):121-125. https://doi.org/10.25789/YMJ.2024.85.30
Views:
24
Email this article 