Pathogenic Mitochondrial DNA Mutations Are Common in the General Population

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.

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…Over the past 5 years, new technologies have been developed to screen for mtDNA mutations, including denaturing high-performance liquid chromatography; 50,51 a detection system using a mismatchspecific DNA endonuclease; 52 the Biplex Invader assay by hybridization of two overlapping oligonucleotides to the target sequence; 53 the matrix-associated laser desorption/ionization time of flight mass spectrometry assay; 54 the pyrosequncing technology to detect and estimate heteroplasmic mtDNA point mutations; 55 and an entire mtDNA resequencing chip: Mitochip. 56,57 The Mitochip uses hybridization for detecting mutations or polymorphisms, so that the probes mtDNA mutation screening for hereditary HL T Kato et al should be designed.…”

Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

“…The most common form of mitochondrial disease is attributed to the pathogenic mtDNA point mutation m.3243A>G in the mt‐tRNA leucine gene ( MTTL‐1 ), estimated to be present in approximately 1 in 400 of the population 3, 4. Clinical syndromes classically associated with the phenotypic expression of the m.3243A>G mutation include mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS), maternally inherited deafness and diabetes (MIDD), and chronic progressive external ophthalmoplegia.…”

Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population

“…This further indicates that we could have missed additional mutation carrying patients using typical phenotype characteristics to delineate the cohort of 238 patients that was tested. Our mutation carriers are highly likely to have MELAS rather than being carriers only: first, they all appeared with ISs; second, they had major phenotypic features of MELAS; third, we found an incidence of 1.7 % that is well-above that was found in general populations (*1 in 1000) [18,19]; and last, individuals carrying MELAS mutation are only rarely asymptomatic [20].…”

“…MELAS main mutation tested in unselected populations was found to be 7/2954 among white people in one study [18] and 4/3168 in neonatal umbilical cord blood samples from sequential live births in the United Kingdom [19]. Interestingly, all seven individuals in the former study had mild to moderate hearing loss [18].…”