Pathogenic Mitochondrial DNA Mutations Are Common in the General Population

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2008 Aug 5

PMID 18674747

Citations 253

Authors

Hannah R Elliott

David C Samuels

James A Eden

Caroline L Relton

Patrick F Chinnery

Affiliations

Soon will be listed here.

Abstract

Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30-0.89%). Of these live births, 0.00107% (95% CI = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The most common mutation was m.3243A-->G. m.14484T-->C was only found on sub-branches of mtDNA haplogroup J. In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of m.14484T-->C on haplogroup J implicates the background mtDNA haplotype in mutagenesis. These findings emphasize the importance of developing new approaches to prevent transmission.

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References

Pyle A, Taylor R, Durham S, Deschauer M, Schaefer A, Samuels D . Depletion of mitochondrial DNA in leucocytes harbouring the 3243A->G mtDNA mutation. J Med Genet. 2006; 44(1):69-74. PMC: 2597915. DOI: 10.1136/jmg.2006.043109. View

Newkirk J, Taylor R, Howell N, Bindoff L, Chinnery P, Alberti K . Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population. Diabet Med. 1997; 14(6):457-60. DOI: 10.1002/(SICI)1096-9136(199706)14:6<457::AID-DIA372>3.0.CO;2-W. View

Schaefer A, McFarland R, Blakely E, He L, Whittaker R, Taylor R . Prevalence of mitochondrial DNA disease in adults. Ann Neurol. 2007; 63(1):35-9. DOI: 10.1002/ana.21217. View

Uusimaa J, Moilanen J, Vainionpaa L, Tapanainen P, Lindholm P, Nuutinen M . Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children. Ann Neurol. 2007; 62(3):278-87. DOI: 10.1002/ana.21196. View

Skladal D, Halliday J, Thorburn D . Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003; 126(Pt 8):1905-12. DOI: 10.1093/brain/awg170. View

Craig K, ELLIOTT H, Keers S, Lambert C, Pyle A, Graves T . Episodic ataxia and hemiplegia caused by the 8993T->C mitochondrial DNA mutation. J Med Genet. 2007; 44(12):797-9. PMC: 2652821. DOI: 10.1136/jmg.2007.052902. View

Chase D, Tawn E, Parker L, Jonas P, Parker C, Burn J . The North Cumbria Community Genetics Project. J Med Genet. 1998; 35(5):413-6. PMC: 1051317. DOI: 10.1136/jmg.35.5.413. View

Odawara M, Sasaki K, Yamashita K . Prevalence and clinical characterization of Japanese diabetes mellitus with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene. J Clin Endocrinol Metab. 1995; 80(4):1290-4. DOI: 10.1210/jcem.80.4.7714102. View

Samuels D, Boys R, Henderson D, Chinnery P . A compositional segmentation of the human mitochondrial genome is related to heterogeneities in the guanine mutation rate. Nucleic Acids Res. 2003; 31(20):6043-52. PMC: 219467. DOI: 10.1093/nar/gkg784. View

10.

Rajasimha H, Chinnery P, Samuels D . Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A-->G mutation in blood. Am J Hum Genet. 2008; 82(2):333-43. PMC: 2427290. DOI: 10.1016/j.ajhg.2007.10.007. View

11.

Yu-Wai-Man P, Griffiths P, Brown D, Howell N, Turnbull D, Chinnery P . The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003; 72(2):333-9. PMC: 379226. DOI: 10.1086/346066. View

12.

Ji L, Hou X, Han X . Prevalence and clinical characteristics of mitochondrial tRNAleu(UUR) nt 3243 A-->G and nt 3316 G-->A mutations in Chinese patients with type 2 diabetes. Diabetes Res Clin Pract. 2001; 54 Suppl 2:S35-8. DOI: 10.1016/s0168-8227(01)00333-3. View

13.

Darin N, Oldfors A, Moslemi A, Holme E, Tulinius M . The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001; 49(3):377-83. View

14.

Cree L, Samuels D, Chuva de Sousa Lopes S, Rajasimha H, Wonnapinij P, Mann J . A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet. 2008; 40(2):249-54. DOI: 10.1038/ng.2007.63. View

15.

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

16.

Klemm T, Neumann S, Trulzsch B, Pistrosch F, Hanefeld M, Paschke R . Search for mitochondrial DNA mutation at position 3243 in German patients with a positive family history of maternal diabetes mellitus. Exp Clin Endocrinol Diabetes. 2001; 109(5):283-7. DOI: 10.1055/s-2001-16348. View

17.

Howell N . Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve?. J Bioenerg Biomembr. 1997; 29(2):165-73. DOI: 10.1023/a:1022690030664. View

18.

t Hart L, Jansen J, Lemkes H, de Knijff P, Maassen J . Heteroplasmy levels of a mitochondrial gene mutation associated with diabetes mellitus decrease in leucocyte DNA upon aging. Hum Mutat. 1996; 7(3):193-7. DOI: 10.1002/(SICI)1098-1004(1996)7:3<193::AID-HUMU2>3.0.CO;2-C. View

19.

Relton C, Daniel C, Hammal D, Parker L, Tawn E, Burn J . DNA repair gene polymorphisms, pre-natal factors and the frequency of somatic mutations in the glycophorin-A gene among healthy newborns. Mutat Res. 2003; 545(1-2):49-57. DOI: 10.1016/j.mrfmmm.2003.09.007. View

20.

Carelli V, Achilli A, Valentino M, Rengo C, Semino O, Pala M . Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet. 2006; 78(4):564-74. PMC: 1424694. DOI: 10.1086/501236. View