ymjЯкутский медицинский журналYakut Medical Journal1813-19052312-1017ЯНЦ КМП10.25789/YMJ.2024.85.30ymj-393Research ArticleСЛУЧАЙ ИЗ ПРАКТИКИCLINICAL CASEГетероплазмия мутации m.3243A>G митохондриальной ДНК в якутской семье с MELAS синдромом: связь с фенотипическими проявлениямиHeteroplasmic mutation of m.3243A>G mitochondrial DNA in the Yakut family with MELAS syndrome: connection with phenotypic manifestationshttps://orcid.org/0000-0002-1395-8256ЗахароваР. Н.ZakharovaR. N.

ЗАХАРОВА Раиса Николаевна – к.м.н., в.н.с.

ZAKHAROVA Raisa Nikolaevna – Ph.D., Leading Researcher, Research Center

https://orcid.org/0000-0003-3385-9471ТихоновД. Г.TikhonovD. G.

ТИХОНОВ Дмитрий Гаврильевич – д.м.н., гл.н.с.

TIKHONOV Dmitry Gavrilyevich – MD, Chief Researcher, Research Center

https://orcid.org/0000-0002-7692-9954ГолубенкоМ. В.GolubenkoM. V.

ГОЛУБЕНКО Мария Владимировна – к.б.н., с.н.с. 

GOLUBENKO Maria Vladimirovna – Ph.D., senior researcher laboratories of population genetics of the Research Institute of Medical Genetics

https://orcid.org/0000-0002-1501-7433СивцеваТ. М.SivtsevaT. M.

СИВЦЕВА Татьяна Михайловна – к.б.н., в.н.с.

SIVTSEVA Tatyana Mikhailovna – Ph.D., Leading Researcher, Research Center

https://orcid.org/0000-0001-8099-2270СеменовС. И.SemenovS. I.

СЕМЕНОВ Сергей Иннокентьевич – д.м.н., в.н.с.

SEMENOV Sergey Innokentievich – MD, Leading Researcher, Research Center

https://orcid.org/0000-0002-4159-500XТаппаховА. А.TappakhovA. A.

ТАППАХОВ Алексей Алексеевич – к.м.н., доцент

TAPPAKHOV Aleksey Alekseevich – Ph.D., Associate Professor, Department of Neurology and Psychiatry

НиколаеваТ. Я.NikolaevaT. Ya.

НИКОЛАЕВА Татьяна Яковлевна – д.м.н., зав. кафедрой 

NIKOLAEVA Tatyana Yakovlevna – MD, head of the Department of Neurology and Psychiatry

https://orcid.org/0000-0003-2746-0608КлимоваТ. М.KlimovaT. M.

КЛИМОВА Татьяна Михайловна – к.м.н., доцент, с.н.с.; с.н.с. 

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

https://orcid.org/0000-0001-9529-2488ОсаковскийВ. Л.OsakovskyV. L.

ОСАКОВСКИЙ Владимир Леонидович – к.б.н., гл.н.с.

OSAKOVSKY Vladimir Leonidovich – Ph.D., Chief Researcher, Research Center

https://orcid.org/0000-0002-6952-3868ФедороваС. А.FedorovaS. A.

ФЕДОРОВА Сардана Аркадьевна – д.б.н., гл.н.с., НИЛ молекулярной биологии 

FEDOROVA Sardana Arkadievna – Dr. Biol. Sci., Chief Researcher, Research Laboratory of Molecular Biology

НИЦ Медицинского ин-та Северо-Восточного федеральн. ун-та им. М.К. АммосоваРоссияMedical Institute of the M.K. Ammosov North-Eastern Federal UniversityRussian FederationНИИ медицинской генетики Томского НИМЦРоссияTomsk National Research Medical CenterRussian FederationМедицинский ин-т СВФУРоссияMedical Institute of the M.K. Ammosov North-Eastern Federal UniversityRussian FederationМИ СВФУРоссияMedical Institute of the M.K. Ammosov North-Eastern Federal UniversityRussian FederationНИЦ Медицинского ин-та Северо-Восточного федеральн. ун-та им. М.К. Аммосова; ЯНЦ КМПРоссияMedical Institute of the M.K. Ammosov North-Eastern Federal University; Yakutsk Science Center for Complex Medical ProblemsRussian FederationИн-т естественных наук СВФУРоссияInstitute of Natural Sciences, M.K. Ammosov North-Eastern Federal UniversityRussian Federation20241802202501121125Copyright © Захарова Р.Н., Тихонов Д.Г., Голубенко М.В., Сивцева Т.М., Семенов С.И., Таппахов А.А., Николаева Т.Я., Климова Т.М., Осаковский В.Л., Федорова С.А., 20252025Захарова Р.Н., Тихонов Д.Г., Голубенко М.В., Сивцева Т.М., Семенов С.И., Таппахов А.А., Николаева Т.Я., Климова Т.М., Осаковский В.Л., Федорова С.А.Zakharova R.N., Tikhonov D.G., Golubenko M.V., Sivtseva T.M., Semenov S.I., Tappakhov A.A., Nikolaeva T.Y., Klimova T.M., Osakovsky V.L., Fedorova S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://ymj.elpub.ru/jour/article/view/393

Впервые генетически верифицирован диагноз MELAS-синдрома в якутской семье с помощью секвенирования митохондриального генома. Подтверждена замена аденина на гуанин в позиции 3243 (m.3243A>G) в в гене tRNALeu(UUR) (MT-TL1). Уровень мутантного аллеля (ге- тероплазмия) у пациентки составил 38,5%, тогда как у матери всего лишь 9,8%, что объясняется являением селекции быстро делящихся клеток крови с низким уровнем мутантных аллелей в течение жизни. Показано, что явление гетероплазмии мтДНК формирует значительную клиническую гетерогенность проявления болезни и демонстрирует сложность постановки диагноза субклинических форм MELAS.

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.

митохондриальные заболеваниясиндром MELASмутация m.3243A>Gmitochondrial diseasesMELAS syndromem.3243A>G mutationИсследование проведено в рамках базовой части государственного за- дания Министерства образования и науки РФ по теме «Генетические осо- бенности населения Северо-Востока России: реконструкция генетической истории, механизмы адаптации и старения, возраст- зависимые и на- следственные заболевания» (FSRG- 2023-0003).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”).ReferencesMELAS-синдром как необычная причина гипопаратиреоза: клиническое наблюдение / Д.Ш. Умярова [и др.]. // Остеопороз и остеопатии. 2018. №3. С. 30-35.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.MELAS syndrome as an unusual cause of hypoparathyroidism: a clinical observation /D.Sh. Umyarova [et al.]. // Osteoporosis and osteopathy. 2018. No.3. P. 30-35.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.).].Неврологические нарушения при митохондриальной энцефаломиопатии – лактатацидозе с инсультоподобными эпизодами (синдроме MELAS) / Д.А. Харламов [и др.] // Рос вестн перинатол и педиат. 2012. №42. – С. 44-50.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.).].Neurological disorders in mitochondrial encephalomyopathy – lactate acidosis with stroke-like episodes (MELAS syndrome) / D.A. Kharlamov [et al.] // Russian Bulletin of perinatology and pediatrics. 2012. No. 4-2. – P. 44-50.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.Ульянова О.В., Куташов В.А. Синдром MELAS: особенности диагностики, течения заболевания и лечения (клинический случай) // Саратовский научно-медицинский журнал. – 2021. №1. – C. 155-159.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:10.1186/1471-2148-13-127Ulyanova O.V., Kutashov V.A. MELAS syndrome: features of diagnosis, course of the disease and treatment (clinical case) // Saratov Scientific Medical Journal. – 2021. No.1. – P. 155-159.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.Analysis of mitochondrial 12S rRNA and tRNASer(UCN) genes in patients with nonsyndromic sensorineural hearing loss from various regions of Russia / L. U. Dzhemilova [et al.] // Russian Journal of Genetics. – 2009. – Vol. 45, No. 7. – P. 861-869. – DOI 10.1134/S1022795409070151.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.Autosomal and uniparental portraits of the native populations of Sakha (Yakutia): implications for the peopling of Northeast Eurasia / S.A. Fedorova, [et al.] // BMC evolutionary biology. 2013. 13:127. doi:10.1186/1471-2148-13-127Goto 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.Bilateral deafness, diabetes, and different types of cardiomyopathy in family members with m.3243A > g mutation: a case report. / F. Seiler, [et al.] // Eur Heart J Case Rep. – 2023. 7(2):ytad073. doi: 10.1093/ehjcr/ytad073.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.Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study / S. Rahman, [et al.] // Am J Hum Genet. – 2001. 68(1). – P.238-40. doi: 10.1086/316930.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.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). P. 651-3. doi: 10.1038/348651a0.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. A7837Kazak mitochondrial genomes provide insights into the human population history of Central Eurasia / A. Askapuli, [et al.] // PLoS One. 2022. 17(11): e0277771. doi: 10.1371/journal. pone.0277771.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.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.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/ s41431-017-0028-8MELAS: Phenotype Classification into Classic-versus-Atypical Presentations / C. Alves, [et al.] // American Journal of Neuroradiology. 2023. – 44(5). – P. 602-610. https://doi.org/10.3174/ajnr.A7837Derenko 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.0015214Mitochondrial disease in adults: recent advances and future promise / Ng YS, [et al.]. // Lancet Neurol. 2021 Jul;20(7):573-584. doi: 10.1016/ S1474-4422(21)00098-3.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.Mitochondrial genomes uncover the maternal history of the Pamir populations / Peng MS, [et al.] // European Journal of Human Genetics. 2018. 26: 124–136. https://doi.org/10.1038/s41431-017-0028-8Picard 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.Origin and Post-Glacial Dispersal of Mitochondrial DNA Haplogroups C and D in Northern Asia / M. Derenko, [et al.] // PLoS One. 2010. 5(12): e15214. doi: 10.1371/journal. pone.0015214Reid 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.Phenotypic heterogeneity in a Chinese family with mitochondrial disease and A3243G mutation of mitochondrial DNA. / Thajeb P, [et al.] // Zhonghua Yi Xue Za Zhi (Taipei). – 2000. 63(1):71-6.Phenotypic heterogeneity in a Chinese family with mitochondrial disease and A3243G mutation of mitochondrial DNA. / Thajeb P, [et al.] // Zhonghua Yi Xue Za Zhi (Taipei). – 2000. 63(1):71-6.Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming / Picard M, [et al.] // Proc Natl Acad Sci U S A. – 2014. 111(38):E4033-42. doi: 10.1073/pnas.1414028111.Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming / Picard M, [et al.] // Proc Natl Acad Sci U S A. – 2014. 111(38):E4033-42. doi: 10.1073/pnas.1414028111.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.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.

The authors declare that there are no conflicts of interest present.