PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring

Hellebrekers, Debby M.E.I.; Wolfe, Rory; Hendrickx, Alexandra T.M.; Coo, I.F.M. de; Die, C E de; Geraedts, J. P. M.; Chinnery, Patrick F.; Smeets, H.

doi:10.1093/humupd/dms008

Cited by 85 publications

(62 citation statements)

References 33 publications

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“…Even so, preimplantation genetic diagnosis for mitochondrial disease has resulted in the birth of healthy children with a lower risk of mitochondrial disease and so provides a promising option for some affected families. For this approach to be successful, however, the mtDNA mutation carrier must produce embryos with heteroplasmy levels below the critical threshold for disease expression; some guidelines have suggested a threshold of 18% (40), but the level will vary depending on the mtDNA mutation.…”

Section: Preimplantation Genetic Diagnosismentioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

225

198

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Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.

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Section: Preimplantation Genetic Diagnosismentioning

confidence: 99%

Recent Advances in Mitochondrial Disease

Craven

Alston

Taylor

et al. 2017

Annu. Rev. Genom. Hum. Genet.

225

198

View full text Add to dashboard Cite

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“…Within the spectrum of mitochondrial diseases, the onset of symptoms can vary according to the nature and level of the mtDNA variation and the requirement for OXPHOS among tissues. A mother affected by mitochondrial disease can be diagnosed for mtDNA heteroplasmy to determine whether she would be at risk of transmitting the disease to her child (Hellebrekers et al 2012). Moreover, healthy mothers can be carriers and transmit a mtDNA defect (Chinnery et al 1998;Spikings et al 2006).…”

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confidence: 99%

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

et al. 2016

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The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sexspecific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation.KEYWORDS mitochondrial DNA; segregation; variants; generations; embryo W HILE the nuclear genome is inherited from both parents, the mitochondrial genome (mtDNA) is only inherited from the population present in the oocyte at fertilization (Chinnery et al. 2000). The porcine mitochondrial genome is 16.7 kb in size and encodes 13 of the subunits of the electron transport chain, which drives ATP synthesis through the biochemical process of oxidative phosphorylation (OXPHOS) (Ursing and Arnason 1998). It also encodes 22 transfer RNAs (tRNAs), which are interspersed between the encoding genes, and 2 ribosomal RNA (rRNA) complexes. mtDNA is located in the mitochondrial matrix and is tethered to proteins, which collectively form the mitochondrial nucleoid (Kucej and Butow 2007). mtDNA is present in multiple copies within cells and these genomes can be polymorphic. Consequently, cells can inherently harbor variant and wild-type (WT) sequences, i.e., heteroplasmic populations, of mtDNA at different frequencies (Wallace and Chalkia 2013).Most mtDNA variants are nonpathogenic (Ramos et al. 2013) but specific nucleotide mutations and large-scale deletions can lead to molecular defects, resulting in a wide range of clinical conditions, known as mitochondrial diseases (McFarland et al. 2007). Within the spectrum of mitochondrial diseases, the onset of symptoms can vary according to Copyright © 2016 Apart from the occurrence o...

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“…As a result, mtDNA mutations are an important cause of a group of devastating inherited diseases (Taylor and Turnbull 2005). To date, over 150 pathogenic mtDNA mutations have been identified, as well as many more polymorphisms of unknown significance (Hellebrekers et al 2012). As human and animal cells have a high mtDNA copy number, wild-type and variant mtDNA genotypes can coexist, a state referred to as heteroplasmy.…”

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confidence: 99%

“…The high mtDNA copy number compensates low-level pathogenic mtDNA mutations and avoids disease manifestation. A pathogenic mtDNA mutation will only manifest if its heteroplasmy value exceeds a certain threshold (Hellebrekers et al 2012). The mtDNA inherits maternally, and a female carrying an mtDNA mutation can transmit this mutation to her offspring through the mtDNA of her oocytes.…”

mentioning

confidence: 99%

Replication Errors Made During Oogenesis Lead to Detectable De Novo mtDNA Mutations in Zebrafish Oocytes with a Low mtDNA Copy Number

et al. 2016

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Of all pathogenic mitochondrial DNA (mtDNA) mutations in humans, 25% is de novo, although the occurrence in oocytes has never been directly assessed. We used next-generation sequencing to detect point mutations directly in the mtDNA of 3-15 individual mature oocytes and three somatic tissues from eight zebrafish females. Various statistical and biological filters allowed reliable detection of de novo variants with heteroplasmy $1.5%. In total, we detected 38 de novo base substitutions, but no insertions or deletions. These 38 de novo mutations were present in 19 of 103 mature oocytes, indicating that 20% of the mature oocytes carry at least one de novo mutation with heteroplasmy $1.5%. This frequency of de novo mutations is close to that deducted from the reported error rate of polymerase gamma, the mitochondrial replication enzyme, implying that mtDNA replication errors made during oogenesis are a likely explanation. Substantial variation in the mutation prevalence among mature oocytes can be explained by the highly variable mtDNA copy number, since we previously reported that 20% of the primordial germ cells have a mtDNA copy number of #73 and would lead to detectable mutation loads. In conclusion, replication errors made during oogenesis are an important source of de novo mtDNA base substitutions and their location and heteroplasmy level determine their significance.

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PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring

Cited by 85 publications

References 33 publications

Recent Advances in Mitochondrial Disease

Recent Advances in Mitochondrial Disease

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

Replication Errors Made During Oogenesis Lead to Detectable De Novo mtDNA Mutations in Zebrafish Oocytes with a Low mtDNA Copy Number

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