Wild-Type Mitochondrial DNA Copy Number in Urinary Cells As a Useful Marker for Diagnosing Severity of the Mitochondrial Diseases

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jul 5

PMID 23826218

Citations 9

Authors

Hui Liu

YiNan Ma

Fang Fang

Ying Zhang

Liping Zou

Yanling Yang

Sainan Zhu

Songtao Wang

Xuefei Zheng

Pei Pei

Lin Li

Hairong Wu

Yang Xiao

Yufeng Xu

Liwen Wang

Yanyan Cao

Hong Pan

Yu Qi

Affiliations

Soon will be listed here.

Abstract

The genotype-phenotype relationship in diseases with mtDNA point mutations is still elusive. The maintenance of wild-type mtDNA copy number is essential to the normal mitochondrial oxidative function. This study examined the relationship between mtDNA copy number in blood and urine and disease severity of the patients harboring A3243G mutation. We recruited 115 A3243G patients, in which 28 were asymptomatic, 42 were oligo-symptomatic, and 45 were poly-symptomatic. Increase of total mtDNA copy number without correlation to the proportion of mutant mtDNA was found in the A3243G patients. Correlation analyses revealed that wild-type mtDNA copy number in urine was the most important factor correlated to disease severity, followed by proportion of mutant mtDNA in urine and proportion of mutant mtDNA in blood. Wild-type copy number in urine negatively correlated to the frequencies of several major symptoms including seizures, myopathy, learning disability, headache and stroke, but positively correlated to the frequencies of hearing loss and diabetes. Besides proportion of mutant mtDNA in urine, wild-type copy number in urine is also an important marker for disease severity of A3243G patients.

Citing Articles

SRSF1 Is Required for Mitochondrial Homeostasis and Thermogenic Function in Brown Adipocytes Through its Control of Ndufs3 Splicing.

Yuan N, Shen L, Peng Q, Sha R, Wang Z, Xie Z Adv Sci (Weinh). 2024; 11(21):e2306871.

PMID: 38569495 PMC: 11151030. DOI: 10.1002/advs.202306871.

Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria.

Pierro E, Perrone M, Franco M, Granata F, Duca L, Lattuada D Life (Basel). 2023; 13(9).

PMID: 37763326 PMC: 10532762. DOI: 10.3390/life13091923.

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.

McCormick E, Lott M, Dulik M, Shen L, Attimonelli M, Vitale O Hum Mutat. 2020; 41(12):2028-2057.

PMID: 32906214 PMC: 7717623. DOI: 10.1002/humu.24107.

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing.

Bris C, Goudenege D, Desquiret-Dumas V, Charif M, Colin E, Bonneau D Front Genet. 2019; 9:632.

PMID: 30619459 PMC: 6297213. DOI: 10.3389/fgene.2018.00632.

mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease.

Grady J, Pickett S, Ng Y, Alston C, Blakely E, Hardy S EMBO Mol Med. 2018; 10(6).

PMID: 29735722 PMC: 5991564. DOI: 10.15252/emmm.201708262.

References

Liu C, Cheng W, Lee C, Ma Y, Lin C, Huang C . Alteration in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies. Acta Neurol Scand. 2006; 113(5):334-41. DOI: 10.1111/j.1600-0404.2006.00586.x. View

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View

Manwaring N, Jones M, Wang J, Rochtchina E, Howard C, Mitchell P . Population prevalence of the MELAS A3243G mutation. Mitochondrion. 2007; 7(3):230-3. DOI: 10.1016/j.mito.2006.12.004. View

Jeppesen T, Schwartz M, Frederiksen A, Wibrand F, Olsen D, Vissing J . Muscle phenotype and mutation load in 51 persons with the 3243A>G mitochondrial DNA mutation. Arch Neurol. 2006; 63(12):1701-6. DOI: 10.1001/archneur.63.12.1701. View

Boyle J, Lew A . An inexpensive alternative to glassmilk for DNA purification. Trends Genet. 1995; 11(1):8. DOI: 10.1016/s0168-9525(00)88977-5. View

Francisci S, Bohn C, Frontali L, Bolotin-Fukuhara M . Ts mutations in mitochondrial tRNA genes: characterization and effects of two point mutations in the mitochondrial gene for tRNAphe in Saccharomyces cerevisiae. Curr Genet. 1998; 33(2):110-6. DOI: 10.1007/s002940050315. View

Yu-Wai-Man P, Sitarz K, Samuels D, Griffiths P, Reeve A, Bindoff L . OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Hum Mol Genet. 2010; 19(15):3043-52. PMC: 2901142. DOI: 10.1093/hmg/ddq209. View

Guillausseau P, Dubois-Laforgue D, Massin P, Laloi-Michelin M, Bellanne-Chantelot C, Gin H . Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD). Diabetes Metab. 2004; 30(2):181-6. DOI: 10.1016/s1262-3636(07)70105-2. View

Durham S, Samuels D, Cree L, Chinnery P . Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A-->G. Am J Hum Genet. 2007; 81(1):189-95. PMC: 1950909. DOI: 10.1086/518901. View

10.

Bentlage H, Attardi G . Relationship of genotype to phenotype in fibroblast-derived transmitochondrial cell lines carrying the 3243 mutation associated with the MELAS encephalomyopathy: shift towards mutant genotype and role of mtDNA copy number. Hum Mol Genet. 1996; 5(2):197-205. DOI: 10.1093/hmg/5.2.197. View

11.

Oka Y, Katagiri H, Ishihara H, Asano T, Kobayashi T, Kikuchi M . Beta-cell loss and glucose induced signalling defects in diabetes mellitus caused by mitochondrial tRNALeu(UUR) gene mutation. Diabet Med. 1996; 13(9 Suppl 6):S98-102. View

12.

Guillausseau P, Massin P, Dubois-Laforgue D, Timsit J, Virally M, Gin H . Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med. 2001; 134(9 Pt 1):721-8. DOI: 10.7326/0003-4819-134-9_part_1-200105010-00008. View

13.

Koga Y, Povalko N, Nishioka J, Katayama K, Yatsuga S, Matsuishi T . Molecular pathology of MELAS and L-arginine effects. Biochim Biophys Acta. 2011; 1820(5):608-14. DOI: 10.1016/j.bbagen.2011.09.005. View

14.

Rinaldi T, Gambadoro A, Francisci S, Frontali L . Nucleo-mitochondrial interactions in Saccharomyces cerevisiae: characterization of a nuclear gene suppressing a defect in mitochondrial tRNA(Asp) processing. Gene. 2003; 303:63-8. DOI: 10.1016/s0378-1119(02)01154-x. View

15.

Shoffner J, Lott M, Lezza A, Seibel P, Ballinger S, Wallace D . Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990; 61(6):931-7. DOI: 10.1016/0092-8674(90)90059-n. View

16.

Ma Y, Fang F, Yang Y, Zou L, Zhang Y, Wang S . The study of mitochondrial A3243G mutation in different samples. Mitochondrion. 2009; 9(2):139-43. DOI: 10.1016/j.mito.2009.01.004. View

17.

Chinnery P, Samuels D . Relaxed replication of mtDNA: A model with implications for the expression of disease. Am J Hum Genet. 1999; 64(4):1158-65. PMC: 1377840. DOI: 10.1086/302311. View

18.

Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K . Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A. 2009; 149A(4):584-7. PMC: 2663596. DOI: 10.1002/ajmg.a.32703. View

19.

Bai R, Wong L . Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: a single-step approach. Clin Chem. 2004; 50(6):996-1001. DOI: 10.1373/clinchem.2004.031153. View

20.

Newton C, Graham A, Heptinstall L, Powell S, Summers C, Kalsheker N . Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989; 17(7):2503-16. PMC: 317639. DOI: 10.1093/nar/17.7.2503. View