The general characteristics of the mtDNA genome and the features of the inheritance of disorders caused by pathogenic variants in this genome were first described in Chapters 2 and 7 but are reviewed briefly here. The small circular mtDNA chromosome is located inside mitochondria and contains only 37 genes (Fig. 1). Unlike nuclear chromosomes, different cell types have a wide range in the copy number of mtDNA. The oocyte at fertilization has ~106 copies, fibroblasts may have thousands of copies, and red blood cells have none. In addition to encoding two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs), mtDNA encodes 13 proteins that are subunits of oxidative phosphorylation.

Fig1. Representative disease-causing variants and deletions in the human mtDNA genome, shown in relation to the location of the genes encoding the 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins of the oxidative phosphorylation complex. OH and Ol are the origins of replication of the two DNA strands, respectively; 12S, 12S ribosomal RNA; 16S, 16S ribosomal RNA. The locations of each of the tRNAs are indicated by the single-letter code for their corresponding amino acids. The 13 oxidative phosphorylation polypeptides encoded by mitochondrial DNA (mtDNA) include components of complex I: NADH dehydrogenase (ND1, ND2, ND3, ND4, ND4l, ND5, and ND6); complex III: cytochrome b (cyt b); complex IV: cytochrome c oxidase I or cytochrome c (COI, COII, COIII); and complex V: ATPase 6 and 8 (A6, A8). The disease abbreviations used in this figure (e.g., MElAS, MERRF, lHON) are explained in Table 1. CPEO, Chronic progressive external ophthalmoplegia; NARP, neuropathy, ataxia, and retinitis pigmentosa. Variants and annotations from MITOMAP (www.mitomap.org).

Table1. Representative Examples of Disorders due to Variants in Mitochondrial DNA and Their Inheritance

Pathogenic variants in mtDNA, and the associated disorders, can be inherited or acquired as somatic mutations. These diseases show distinctive patterns of inheritance due to three features of mtDNA:

 • Maternal inheritance

 • Homoplasmy and heteroplasmy

• Replicative segregation

The maternal inheritance of mtDNA; reflects the fact that sperm mtDNA are generally eliminated from the embryo so that mtDNA is inherited entirely from the mother. Paternal inheritance has been well documented in only one instance, and this case may rep resent a unique failure in the clearance of paternal mtDNA. Replicative segregation refers to the fact that the multiple copies of mtDNA in each mitochondrion replicate and assort randomly among newly synthesized mitochondria, which in turn are distributed randomly between the daughter cells. This occurs in both mitotic and meiotic divisions and impacts the transmission of heteroplasmy between generations (a phenomenon known as a germline bottleneck), which is described in greater detail later.

The 74 polypeptides of the oxidative phosphorylation complex not encoded in the mtDNA are encoded by the nuclear genome, which contains the genes for most of the estimated 1500 mitochondrial proteins. To date, more than 300 nuclear genes are associated with disorders of the respiratory chain. Thus diseases of oxidative phosphorylation arise not only from pathogenic variants in the mitochondrial genome but also from variants in nuclear genes that encode oxidative phosphorylation components. Furthermore, the nuclear genome encodes up to 200 proteins required for the maintenance and expression of mtDNA genes or for the assembly of oxidative phosphorylation protein complexes. Defects in many of these nuclear genes can also lead to disorders with the phenotypic characteristics of mtDNA diseases, but of course the patterns of inheritance in these cases are those typically seen with other mendelian disorders.

Diseases Caused by Pathogenic Variants in mtDNA

The sequence of the mtDNA genome and the presence of pathogenic variants in mtDNA have been known for over 4 decades. The disorders are not uncommon, and the prevalence has been shown, in at least one population, to be ~1 per 5000. The range of clinical disease resulting from mtDNA is diverse (Fig. 2), although neuromuscular disease predominates. Nearly 100 different disease-related variants have been identified in mtDNA, in addition to more than 100 rearrangements that cause disease. Representative pathogenic variants and the diseases associated are presented in Fig. 1 and Table 1. In general, as illustrated in the sections to follow, three types of variants have been identified in mtDNA: rearrangements that generate deletions or duplications of the mtDNA molecule, point variants in tRNA or rRNA genes that impair mitochondrial translation, and missense variants in the coding regions of genes that alter the activity of an oxidative phosphorylation protein.

Fig2. The range of affected tissues and clinical phenotypes associated with variants in mitochondrial DNA (mtDNA). (Modified from Chinnery PF, Turnbull DM: Mitochondrial DNA and disease, Lancet 354:SI17–SI21, 1999.)

Deletions of mtDNA and Disease. In many cases, mtDNA deletions that cause disease, such as Kearns Sayre syndrome (see Table 1), are inherited from an unaffected mother who carries the deletion in her oocytes but generally not elsewhere, an example of gonadal mosaicism. Under these circumstances, disorders caused by mtDNA deletions appear to be sporadic because oocytes carrying the deletion are relatively rare. In ~5% of cases, the mother may be affected and transmit the deletion. The reason for the low frequency of transmission is uncertain, but it may simply reflect the fact that women with a high proportion of the deleted mtDNA in their germ cells have such a severe phenotype that they rarely reproduce.

Mitochondrial tRNA and rRNA Are Associated With Disease. Pathogenic variants in the tRNA and rRNA genes of mtDNA are significant because they illustrate that not all disease-causing variants in humans occur in genes that encode proteins (Case 33). Unlike nuclear tRNA and rRNA, which are present at high copy number in the chromosomes, the mitochondrial genes encoding these RNAs exist at unique locations in the genome (see Fig. 1) so that single nucleotide variants can disrupt their function. Fifty pathogenic variants have been identified in 15 of the 22 tRNA genes of the mtDNA, and they are the most common cause of oxidative phosphorylation abnormalities in humans (see Fig. 1 and Table 1).

Pathogenic tRNA variants include 11 different substitutions in the tRNA^leu(UUR) gene, some of which, like the m.3243A>G variant, cause a phenotype referred to as MElAS, an acronym for mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (see Fig. 1 and Table 1); others are associated predominantly with myopathy. The m.3243A>G variant, for reasons that are not entirely clear, is the most commonly observed mitochondrial pathogenic variant in clinical practice. It is only found in a heteroplasmic state, and the homoplasmic state is presumed to be lethal. An example of an rRNA variant causing dis ease is the m.1555A>G variant in the 12S ribosomal RNA. This variant causes sensorineural prelingual deaf ness after exposure to aminoglycoside antibiotics and illustrates an important rule for homoplasmic variants, which is that they must either be incompletely penetrant or must allow females to survive to reproduction; otherwise, they would be eliminated from the population.

The Phenotypes of Mitochondrial Disorders

Oxidative Phosphorylation and mtDNA Diseases. Mitochondrial diseases generally affect tissues that depend on intact oxidative phosphorylation to satisfy high demands for metabolic energy. This phenotypic focus reflects the central role of the oxidative phosphorylation complex in the production of ATP. The evidence that mechanisms other than decreased energy production contribute to the pathogenesis of mtDNA diseases is either indirect or weak, but the generation of reactive oxygen species as a byproduct of faulty oxidative phosphorylation may also contribute to the pathology of mtDNA disorders. A substantial body of evidence indicates that there is a phenotypic threshold effect associated with mtDNA heteroplasmy ; a critical threshold in the proportion of mtDNA molecules carrying the detrimental variant must be exceeded in cells from the affected tissue before clinical disease becomes apparent. The threshold for the appearance of disease is dependent upon the nature of each variant and its impact on the underlying gene.

The neuromuscular system is most commonly affected by mitochondrial diseases; the consequences can include encephalopathy, myopathy, ataxia, retinal degeneration, and loss of function of the external ocular muscles. Mitochondrial myopathy is characterized by ragged-red (muscle) fibers, a histologic phenotype due to the proliferation of structurally and biochemically abnormal mitochondria in muscle fibers. The spectrum of mitochondrial disease is broad and, as illustrated in Fig. 2, may include liver dysfunction, bone mar row failure, pancreatic islet cell deficiency and diabetes, deafness, and other disorders.

Unexplained and Unexpected Phenotypic Variation in mtDNA Diseases. As seen in Table 1, heteroplasmy is the rule for many mtDNA diseases. Heteroplasmy leads to an unpredictable and variable fraction of disease associated mtDNA being present in any particular tissue, undoubtedly accounting for much of the pleiotropy and variable expressivity of mtDNA mutations. An example is provided by the m.3243A>G substitution in the tRNA^leu(UUR) gene, previously mentioned in the context of the MElAS phenotype. It also leads to maternally inherited diabetes and deafness in some families, whereas in others it causes a disease called chronic progressive external ophthalmoplegia. Moreover, a very small fraction (G substitution.

Disorders of mtDNA Replication

 Because both the nuclear and mitochondrial genomes contribute polypeptides to oxidative phosphorylation, it is not surprising that the phenotypes associated with defects in nuclear genes can be clinically indistinguishable from those due to mitochondrial genes. One additional concept of importance to disease is that the mtDNA itself depends on nuclear genome–encoded proteins for its replication and the maintenance of its integrity.

The medical consequence of this dependency is diseases with mendelian inheritance patterns (dominant or recessive), due to variants in nuclear genes, that have their impact on the mtDNA. An example of this class of disorders is the mtDNA depletion syndromes, which result from pathogenic variants in any of 17 nuclear genes that lead to a reduction in the number of copies of mtDNA (both per mitochondrion and per cell) in various tissues. Some of the affected genes encode proteins required to maintain nucleotide pools or to metabolize nucleotides appropriately in the mitochondrion. One example of a mitochondrial depletion syndrome is Alpers syndrome, which is a recessive disorder caused by pathogenic variants in DNA polymerase γ (POLG). POLG is the DNA-dependent DNA polymerase that replicates mtDNA, and variants in this gene can cause loss of mtDNA but may also lead to excess mutations or rearrangements in mtDNA.

Environmental Influences Modify the Phenotype of mtDNA Diseases. Although heteroplasmy is a major source of phenotypic variability in mtDNA diseases, additional factors, including environmental stressors, also play a role. Strong evidence for environ mental influence is provided by families carrying variants associated with leber hereditary optic neuropathy (LHON; see Table 1), which is generally homoplasmic (thus ruling out heteroplasmy as the explanation for the observed phenotypic variation). LHON is expressed phenotypically as rapid, painless bilateral loss of central vision due to optic nerve atrophy in young adults (see Table 1 and Fig. 1).

There is a striking increase in the penetrance of the disease in males; ~50% of male carriers but only ~10% of female carriers of an LHON variant develop symptoms. Studies of large numbers of individuals have strongly implicated that cigarette smoking, and possibly alcohol consumption, drives this discrepancy in risk. This suggests that environmental stressors causing oxidative injury may play an important and synergistic role in determining the penetrance of a mitochondrial variant. It has additionally been suggested that interactions with nuclear-encoded variants may also alter the risk of developing LHON symptoms.

Problems in Therapy for mtDNA-Associated Disorders. Mitochondrial disorders lag other diseases in the development of new therapies based on genetic manipulation. For diseases due to mtDNA there are two critical drivers of this problem. The first is that mitochondrial disease tends to affect many tissues simultaneously, so approaches to correction have to be applied across the whole patient rather than to a single organ or tissue. The second, and more remarkable challenge, is that genetic manipulation of human mtDNA is largely impossible with current technologies. Mitochondria are impermeable to nucleic acids (DNA and RNA), so techniques of mutagenesis that rely on recombination are not effective, even when used on isolated cells in a laboratory. A related challenge is that there are no viruses that infect the mitochondrion, so genetic delivery systems will need to be developed rather than adapted from existing viruses.

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مواضيع ذات صلة

The APOE Gene Is an Alzheimer Disease Susceptibility Locus

The Genetics of Alzheimer Disease

Molecular Testing for Spinal Muscular Atrophy

Genetics of Spinal Muscular Atrophy

The Phenotypes of Spinal Muscular Atrophy

Chondrodysplasias are Caused by Mutations in Genes Encoding Type II Collagen & Fibroblast Growth Factor Receptors

The Genetics of Osteogenesis Imperfecta

Molecular Abnormalities of Collagen in Osteogenesis Imperfecta

Prenatal Diagnosis of Hereditary Genetic Diseases

Prenatal Diagnosis of Non-hereditary Genetic Diseases

Clinical Applications of Gene Testing in Muscular Dystrophy

The Genetics of Duchenne Muscular Dystrophy and Becker Muscular Dystrophy