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Reproduction
Published in Gary Chan Kok Yew, Health Law and Medical Ethics in Singapore, 2020
The issue of mitochondrial donation has been explored in Singapore with a view to preventing the transmission of mitochondrial diseases from a woman to her offspring. The UK Parliament has passed the Department of Health’s draft Human Fertilisation and Embryology (Mitochondrial Donation) Regulations in 2015 to allow mitochondrial donation for the prevention of serious mitochondrial diseases. Singapore’s BAC (2018) Consultation Paper on mitochondrial genome replacement therapy (MGRT) sought the views of the public as to whether to allow women suffering from various mitochondrial diseases108 the chance to bear genetically related children free from those diseases through egg or embryo manipulation using one or more of the MGRT techniques.109 If successful, the application of the techniques can prevent or mitigate foreseeable injuries to the unborn children. One main concern, however, relates to health risks to the child due to potential incompatibility between the nuclear and mitochondrial DNA. The other is the notion of the “three-parent child” who will inherit genetic material from two prospective parents as well as the donor though the Consultation Paper noted that the nuclear DNA from the prospective parents would likely outweigh the amount of mitochondrial DNA from the donor.110
Pearson syndrome
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
A syndrome was first described in 1979 by Pearson and colleagues [1] in which four unrelated patients had refractory sideroblastic anemia with variable neutropenia and thrombocytopenia, and clinical and pathologic evidence of pancreatic dysfunction. One of these patients later developed Kearns–Sayre syndrome [2]. In 1991, study of this patient by McShane and colleagues [3] revealed a 4.9-kb deletion in mitochondrial DNA. This 4977-bp deletion was located between nt 8488 and nt 13,460. This deletion was also that most commonly observed in patients with Kearns–Sayre syndrome. The same deletion (Figure 55.1) had been reported in 1988 by Rotig and colleagues in an infant with Pearson syndrome [4]. Rotig and colleagues [5] have since studied a larger series of nine patients with Pearson syndrome, including one of Pearson's original patients; five had the previously identified 4.9-kb deletion, and four had distinctly different deletions in the same area of the genome. A consistent feature was the occurrence of direct repeats at the boundaries of the deletions [6], providing a possible mechanism for recombinations. Rotig and her colleagues [7] have since found a patient in whom there was an insertion, as well as a deletion in the mitochondrial DNA. In all patients studied, there was heteroplasmy of normal and deleted mitochondrial genomes.
Genetic counselling in Mendelian disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The mitochondria are the principal cell components outside the nucleus to contain DNA, which is present in the form of a small, circular genome that can replicate and which is quite independent of the mechanisms controlling chromosomal DNA. The usual sequence of the mitochondrial genome is known, as are many disease-associated mutations and the extensive variation within the (rather small) non-coding region, of value in studies on population history (including migration and ancestry). As well as the various RNAs required for protein synthesis, the mitochondrial genome determines the proteins of a series of key enzymes involved in oxidative phosphorylation, although other such enzymes are also produced by genes in the nucleus. Mitochondrial DNA is, for practical purposes, exclusively maternal in origin, with no process involving recombination and a negligible contribution from sperm.
Forensic evaluation of mitochondrial DNA heteroplasmy in Gujarat population, India
Published in Annals of Human Biology, 2022
Mohammed H. M. Alqaisi, Molina Madhulika Ekka, Bhargav C. Patel
The findings of this study indicate that point heteroplasmic positions are more prevalent in mutation-prone sites. However, they can be present throughout the mitochondrial genome. As one of the key observations, for example, np16093 demonstrated heteroplasmy in the blood sample that was not found in the reference buccal sample. This condition should be considered when analysing results in forensic cases where the mutation is not excluded due to its site-specific nature. Additionally, the level of mtDNA PH varied both within and between individuals. We detected a higher frequency of heteroplasmy in the analysis of blood samples than in buccal samples. Thus, several more reference samples from different tissues of the suspect should always be analysed in forensic mtDNA investigations before a conclusive result can be drawn. On the other hand, because heteroplasmy was detected in the same position in both tissues of an individual, this implies that heteroplasmy can actually increase the discriminating power of forensic mtDNA analysis.
Maternal spindle transfer for mitochondrial disease: lessons to be learnt before extending the method to other conditions?
Published in Human Fertility, 2022
Charalampos Siristatidis, Themis Mantzavinos, Nikos Vlahos
Drawing on the rationale of altering the mitochondrial genome/manipulating mtDNA, an encouraging option for mitochondrial dysfunction and failure of organ and tissue functions is gene modification and editing using mtDNA (Aushev & Herbert, 2020). Promising methods include RNA-free DddA-derived cytosine base editors, enabling the precise manipulation of mtDNA resulting in changes in respiration rates and oxidative phosphorylation (Mok et al., 2020; Wang & Wang 2020), in the (CRISPR)/Cas9 system, through the development of mitoCas9 with specific localisation to the mitochondria (Jo et al., 2015) and re-engineered protein-only nucleases, such as mtZFN and mitoTALEN (Gammage et al., 2018). Nevertheless, further studies are required prior to implementing this technique in all cell types, organelles, and various diseases as a new gene therapy for mtDNA diseases.
Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment
Published in Expert Opinion on Therapeutic Targets, 2020
Saeed Mehrzadi, Karim Hemati, Russel J. Reiter, Azam Hosseinzadeh
Each cell may contain hundreds to thousands of mtDNA distributed within hundreds of mitochondria; all the mtDNA molecules are identical in the normal state, which is known as homoplasmy. Due to the polyploidy of the mitochondrial genome, a mixture of two or more mtDNA may coexist within a cell, which is termed as heteroplasmy [94]. The mtDNA molecules have a very high rate of mutation, due to the lack of histones, inefficient repair system and proximity to where ROS are produced [95]. Mutations may affect all copies of mtDNA (homoplasmic mutation) or exist only in some copies of mtDNA (heteroplasmic mutation) [96]. Although the correlation between genotype and phenotype is complex in mitochondrial disorders, the contribution of mtDNA mutation to disease expression is clear [97]. In general, mtDNA mutations cause a clinically observable phenotype only if the proportion of mutant mtDNA exceeds a high threshold value, often 80–90% [98]. Most of homoplasmic mtDNA mutations are neutral polymorphisms but some of them or combinations of them, known as mtDNA haplogroups may be associated with the onset or progression of AMD. Case-control studies from the United States (US) and Australia have reported that mitochondrial polymorphisms (A73 G, A11812 G, A14233 G, A4917 G and T16126 C, among others) and haplogroups (H, J, U and T) may be important risk factors for the development of AMD [73,99–101].