John Wiley & Sons, Ltd.

ELS subject area: Genetics and Disease

How to cite: Ghezzi, Daniele; and Zeviani, Massimo (April 2011) Mitochondrial Disorders: Nuclear Gene Mutations. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0005540.pub2

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Mitochondrial Disorders: Nuclear Gene Mutations

Daniele Ghezzi, The Foundation "Carlo Besta" Institute of Neurology, Milan, Italy

Massimo Zeviani, The Foundation "Carlo Besta" Institute of Neurology, Milan, Italy

Based in part on the previous version of this Encyclopedia of Life Sciences (ELS) article, Mitochondrial Disorders: Nuclear Gene Mutations by Massimo Zeviani.

In addition to mutations of mitochondrial deoxyribonucleic acid (mtDNA), many mitochondrial syndromes are due to abnormalities in nuclear genes related to oxidative phosphorylation (OXPHOS). Nuclear genes encode hundreds of proteins directly involved in mitochondrial OXPHOS or linked to other metabolic pathways that are related to OXPHOS, such as the tricarboxylic acid (TCA) cycle and fatty acids ß-oxidation, cell signalling and apoptosis. Although the identification of mutations in mtDNA has become relatively easy because its small size and the nearly complete elucidation of its sequence polymorphisms, the analysis of nuclear disease genes is still a formidable challenge. However, with the recent improvement in technology throughput and bio-computational power, this scenario is rapidly changing. The discovery of several OXPHOS-related human genes and the identification of mutations responsible for different clinical syndromes indicate that the majority, but not all, of the inherited mitochondrial disorders are due to nuclear genes encoding proteins targeted to mitochondria.

Key Concepts:

• Mitochondria are the principal intracellular source of energy through the production of ATP by oxidative phosphorylation (OXPHOS).
• Mitochondria contain their own genome, a small, circular double-stranded DNA (mtDNA).
• mtDNA contains 13 genes encoding subunits of the respiratory chain complexes and 24 genes encoding 2 ribosomal and 22 transfer RNAs, which are necessary to carry out intramitochondrial translation.
• Mitochondria depend on the nucleus for the supply of all of the other OXPHOS proteins as well as the factors necessary for replication, repair, transcription, translation, maintenance of mtDNA and for the biogenesis, shaping, fusion and fission of the organelles.
• Mitochondrial-inherited diseases may present with a vast range of symptoms, severity, age of onset and outcome.
• Because of its dual genetic control, OXPHOS disorders can be due to mutations in mtDNA or nuclear DNA genes.
• Recent epidemiological studies show that mitochondrial disorders have a minimal prevalence of 1:5000.

Introduction

The term 'mitochondrial disorders' is to a large extent applied to the clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism, that is, oxidative phosphorylation (OXPHOS). OXPHOS is carried out in the inner mitochondrial membrane by the five enzymatic complexes of the respiratory chain. From a genetic standpoint, the respiratory chain is unique, as it is formed through the complementation of two separate genetic systems, the nuclear and the mitochondrial genomes. Because of this dual genetic control, OXPHOS disorders can be due to mutations in mitochondrial deoxyribonucleic acid (mtDNA) or nuclear DNA genes encoding either structural components of the five respiratory chain complexes or factors controlling their expression, assembly, function and turnover (Zeviani and Lamantea, 2006).

The most relevant contribution to the elucidation of the molecular basis of mitochondrial disorders has come from the discovery of an impressive and ever-expanding number of pathogenic mutations of mtDNA. In spite that nuclear gene products account for more than 90% of the mitochondrial proteins related to OXPHOS, the number of mitochondrial disorders caused by genetically defined defects of nuclear genes is still small (although continuously increasing). Most of the cases in which an mtDNA mutation cannot be found are classified as mitochondrial on the basis of a biochemical defect or of the observation of typical morphological clues or of a combination of the two.

Clinical Considerations

The clinical presentation of defects of the respiratory chain is heterogeneous, with onset ranging from neonatal to adult life (Zeviani and Lamantea, 2006). The clinical features include fatal infantile multisystem syndromes, encephalomyopathies or isolated myopathies sometimes associated with cardiomyopathies. In paediatric patients, the most frequent clinical features are severe psychomotor delay, generalised hypotonia, lactic acidosis and signs of cardiorespiratory failure, but additional clinical features and new syndromes are continuously reported (Debray et al., 2008).

Patients with later onset usually show signs of myopathy associated with variable involvement of the central nervous system (CNS) (ataxia, hearing loss, seizures, polyneuropathy, pigmentary retinopathy and, more rarely, movement disorders). Other patients complain only of muscle weakness or wasting with exercise intolerance.

In infants and children, the most common clinical and neuropathological presentation is that of Leigh syndrome (LS). Affected infants show severe psychomotor delay, cerebellar and pyramidal signs, dystonia, respiratory abnormalities, incoordination of ocular movements and recurrent vomiting. Ragged-red fibres are absent. Magnetic resonance imaging (MRI) shows the typical neuropathological findings that define this condition: symmetric lesions usually involve the medulla, the pontine tegmentum and the periaqueductal region and, in the cerebellum, the dentate nuclei and the deep white matter surrounding these nuclei. Basal ganglia and posterior fossa structures may be involved simultaneously (Figure 1).

Figure 1 Brain magnetic resonance images of a patient affected by Leigh Syndrome. (a) Transverse T2-weighted image showing symmetric hyperintense necrotic lesions in the basal ganglia (arrows). (b) Coronal T2-weighted image showing cortical atrophy. (c) A 1H-spectroscopy of the voxels encircled in the brain sections displayed in the upper panels, shows a marked accumulation of lactate (arrow).

LS is clearly a genetically heterogeneous entity. In some cases, it is attributable to mtDNA mutations; in others, the defect is X-linked or sporadic, as in the case of the defect of the E1 a subunit of pyruvate dehydrogenase (PDH). In still other cases, it is attributable to an autosomal recessive defect of a nuclear, OXPHOS-related gene.

In any case, all defects described to date in LS patients affect terminal oxidative metabolism and are likely to impair energy production. The typical neuropathological findings of LS are therefore the expression of the damage produced by faulty oxidative metabolism on the developing brain, irrespective of the specific biochemical or genetic causes (Di Mauro and De Vivo, 1996, MIM 256000).

Genetically Defined Defects of Oxidative Phosphorylation-related Nuclear Genes

Nuclear gene defects related to mitochondrial disorders can be classified into four groups:

• Defects of nuclear genes encoding structural components of respiratory chain complexes.
• Defects of genes encoding factors involved in the assembly of respiratory chain complexes.
• Defects of genes altering the stability of mtDNA.
• Defects of genes encoding factors involved in metabolic pathways influencing the biogenesis of mitochondria, including OXPHOS.

In the first three groups are disorders that are clearly associated with a specific biochemical defect of one of the respiratory chain complexes (Figure 2). The fourth group includes protein products that play a role in different mitochondrial metabolic pathways that are indirectly associated with the mitochondrial energy pathway. In these cases, the pathogenesis cannot be attributed to a specific OXPHOS defect, although abnormalities of the respiratory chain can contribute to the development of organ impairment and clinical phenotype. Table 1 summarises the general classification of the genetically defined defects of OXPHOS-related nuclear genes.

Figure 2 Frequency of biochemical deficiencies in mitochondrial respiratory chain (MRC) complexes. The data were obtained from a total of 239 skeletal muscle biopsies, 75 of which showed reduced activities, analysed in the Unit of Molecular Neurogenetics, Institute of Neurology 'C. Besta', Milan, Italy (E. Lamantea, personal communication).

Table 1 Nuclear disease genes in mitochondrial disorders