All the patterns of inheritance described thus far are explained by variants in the nuclear genome, in either autosomal or X-linked genes. However, some inherited diseases that do not show patterns typical of mendelian inheritance are caused by pathogenic variants in the mitochondrial genome (mtDNA), which manifest strictly maternal inheritance. Disorders caused by pathogenic variants in mtDNA have several unusual features that result from the unique characteristics of mitochondrial biology and function.

As introduced in Chapter 2, not all the RNA and protein synthesized in a cell are encoded in the DNA of the nucleus; a small but important fraction is encoded by genes in mtDNA. The mitochondrial genome con sists of 37 genes that encode 13 subunits of enzymes involved in oxidative phosphorylation, as well as ribosomal RNAs and transfer RNAs required for translating the transcripts of the mitochondria-encoded polypeptides. Because mitochondria are essential to the normal functioning of nearly all cells, disruption of energy pro duction by pathogenic variants in mtDNA often results in severe disease, affecting many different tissues. Thus, pleiotropy is the rule, not the exception, in mitochondrial disorders.

More than 100 different pathogenic variants have been identified in mtDNA that can cause a range of human diseases—often involving the central nervous and musculoskeletal systems, such as myoclonic epilepsy with ragged-red fibers. In this section we will focus on the distinctive pattern of inheritance related to three unusual features of mtDNA: maternal inheritance, replicative segregation, and homoplasmy and heteroplasmy.

Maternal Inheritance of mtDNA

The first defining characteristic of the genetics of mtDNA is its maternal inheritance. Sperm mitochondria are generally not present in the zygote so that only the maternal mtDNA is transmitted to the next generation. Thus, the children of a female who has an mtDNA variant may inherit it, whereas none of the offspring of a male carrying the same variant will. Pedigrees of such disorders are quite distinctive, as shown by the strictly maternal inheritance of an mtDNA variant causing Leber hereditary optic neuropathy (Fig. 1). Although maternal inheritance is the general expectation, at least one instance of paternal inheritance of mtDNA has occurred in a patient with a mitochondrial myopathy. Consequently, in individuals with apparently sporadic mtDNA mutations, the rare occurrence of paternal mtDNA inheritance must be considered (Box 1).

Fig1. Pedigree of Leber hereditary optic neuropathy, a form of adult-onset blindness caused by a defect in mitochondrial DNA. Inheritance is only through the maternal lineage, in agreement with the known maternal inheritance of mitochondrial DNA. Note that no affected male transmits the disease.

Box1. CHARACTERISTICS OF MITOCHONDRIAL INHERITANCE

Replicative Segregation

A second feature of the mitochondrial genome is the stochastic nature of segregation during mitosis and meiosis. The number of mtDNA copies per cell is not fixed and is substantially higher than the number of nuclear DNA copies, with cells having as many as hundreds of thousands of mtDNA copies. In addition there is no fixed phase of the cell cycle for the replication of mtDNA. At cell division, the copies of mtDNA in each of the mitochondria in each cell sort randomly to the daughter cells, in stark contrast to the highly predictable and programmed segregation of the 46 nuclear chromosomes. This process is known as replicative segregation and can result in significant variability in manifestations of mitochondrial disorders among different tissues and/or individuals.

Homoplasmy and Heteroplasmy

The presence of a high copy number creates an additional distinctive feature in the genetics of mtDNA. The terms heterozygous and homozygous, used to describe the presence of one or two allelic variants of a nuclear gene, are inexact for mtDNA. Instead, the term for the uniform presence of an identical mitochondrial sequence is homoplasmic. When a variant sequence of mtDNA is also present, within a cell, tissue, or organism, the term used to describe this is heteroplasmic. When a sequence variant first occurs in the mtDNA, it is present in only one of the mtDNA molecules in a mitochondrion. As mtDNA replicates, the mitochondria undergo fission and fusion, and the variant and wild-type DNA are distributed randomly into daughter organelles, which – simply by chance – may contain different proportions of the two allelic variants. The cell, which now contains mitochondria containing different mixtures of mtDNAs, in turn distributes those mitochondria randomly to its daughter cells. Daughter cells may thus have different levels of heteroplasmy (Fig. 2). A key feature of the heteroplasmic state is that the ratio of the two allelic variants is not fixed over time and may change with further replication and cell division.

Fig2. Replicative segregation of a heteroplasmic mitochondrial variant. Random partitioning of variant and wild-type mtDNA through multiple rounds of mitosis produces a collection of daughter cells with wide variation in heteroplasmy. Cell and tissue dysfunction results when the fraction of mitochondria that are carrying a variant exceeds a threshold level. N, Nucleus.

Because the phenotypic expression of a pathogenic variant in mtDNA depends on a quantitative value—the relative proportions of normal- and pathogenic-allele- bearing mtDNA in the cells making up different tissues—reduced penetrance and variable expression are typical features of mitochondrial disorders. Most pathogenic variants in mtDNA are only present and transmitted in a state of heteroplasmy, since they would reduce reproductive fitness to 0 if they were homoplasmic. The exceptions (including Leber hereditary optic neuropathy as described earlier) cause disorders that are either incompletely penetrant or are not reproductively lethal.

Maternal inheritance in the presence of heteroplasmy in the mother is associated with additional features of mtDNA genetics that are of medical significance. First, the number of mtDNA molecules within developing oocytes is reduced before being subsequently amplified to the massive number (up to 10⁶ copies) seen in mature oocytes. This restriction and subsequent amplification of mtDNA during oogenesis is termed the mitochondrial genetic bottleneck. Consequently, variability in the proportion of variant mtDNA molecules seen in the offspring of a mother with heteroplasmy arises, at least in part, from the sampling of a reduced subset of the mtDNAs after the mitochondrial bottleneck that occurs in oogenesis. The heteroplasmy of the resulting oocytes is a distribution of values based on the heteroplasmy of the mother herself. As might be expected, mothers with a high heteroplasmy for a pathogenic variant are more likely to have clinically affected offspring than are mothers with a lower proportion. Mothers may also have offspring who, by chance, are homoplasmic for the absence of a pathogenic variant.

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مواضيع ذات صلة

Genetic Screening in Populations

Genetic Counseling for Preconception and Prenatal Diagnosis and Screening

Fetal Surgical and Medical Interventions

X-Linked Inheritance

Preconception Genetic Screening and Testing

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects