Mutations in nuclear genes affecting mtDNA maintenance

Diseases associated with multiple large-scale mtDNA deletions, and diseases associated with quantitative loss of mtDNA, so-called depletion, show Mendelian inheritance indicating that these mtDNA defects are secondary to nuclear gene mutations.

The first description of a disease with autosomal-dominant inheritance and multiple mtDNA deletions goes back to 1989 (Zeviani et al., 1989). Multiple mtDNA deletions have been associated with several clinical manifestations, which in most cases present after the first decade of life. The most common, albeit not constant, symptom is progressive external ophthalmoplegia (PEO) with the variable addition of exercise intolerance, recurrent myoglobinuria, ataxia, parkinsonism, major depression, peripheral neuropathy, hypogonadism and cardiomyopathy (Zeviani et al., 1990; Cormier et al., 1991; Ohno et al., 1991; Servidei et al., 1991; Haltia et al., 1992; Suomalainen et al., 1992a; Prelle et al., 1993; Checcarelli et al., 1994; Kawashima et al., 1994; Takei et al., 1995; Ville-Ferlin et al., 1995; Bohlega et al., 1996; Campos et al., 1996a; Chalmers et al., 1996; Fabrizi et al., 1996; Melberg et al., 1996a; Suomalainen et al., 1997; Carrozzo et al., 1998; Federico et al., 1998; Melberg et al., 1998; Nishizuka et al., 1998). As in disorders due to single large-scale deletions, mitochon-drial myopathy with COX-deficient RRF is usually, but not always, present in autosomal-recessive or -dominant PEO with multiple mtDNA deletions. Biochemical analysis typically shows reduction in the partially mtDNA-encoded respiratory chain complexes I, III and IV (Suomalainen et al., 1992a). A variable proportion of mtDNA with deletions are found in postmitotic tissues such as skeletal muscle, myocardium and CNS (Suoma-lainen et al., 1992a; Moslemi et al., 1999). The cerebellum usually shows a lower proportion of mtDNA with deletions than other brain regions. Multiple deletions are not found in cultured myoblasts and they are considered somatic mutations. In muscle tissue the deletions are clonally expanded in muscle fiber segments, with one unique deletion in each fiber segment (Moslemi etal., 1996).

The genes, which are associated with multiple mtDNA deletions or mtDNA depletion are either involved in mtDNA replication and/or play a role in mitochondrial nucleotide metabolism. Several different nuclear gene mutations have been identified in adPEO with multiple mtDNA deletions.

The first identified gene associated with this syndrome is encoding the muscle-heart specific mitochondrial adenine nucleotide translocator 1 (ANT1; Kaukonen et al., 2000; Agostino et al., 2003). How the defective ANT1 causes mtDNA deletions is not known, but various mechanisms have been proposed (Chen, 2002; Fontanesi et al., 2004).

The second gene that was demonstrated to be associated with adPEO is C10orf2, encoding a mitochondri-al protein similar to phage T7 primase/helicase (gp4) named Twinkle (Spelbrink et al., 2001; Agostino et al., 2003; Deschauer et al., 2003b). In-vitro experiments have demonstrated that Twinkle is the helicase at the mitochondrial DNA replication fork and that it is essential for mtDNA replication (Korhonen et al., 2004). Studies in mice have shown that Twinkle is essential for mtDNA maintenance, and may be a key regulator of mtDNA copy number (Tyynismaa et al., 2004).

The third gene associated with PEO and multiple mtDNA deletions is encoding mtDNA polymerase g (POLG1), which is the only mtDNA polymerase in mitochondria (Van Goethem et al., 2001). POLG1 mutations may be either dominant or recessive, and have emerged as the major cause of PEO with multiple mtDNA deletions, frequently in combination with manifestations from CNS and other organs (Van Goethem et al., 2001; Lamantea et al., 2002b; Van Goethem et al., 2002; Di Fonzo et al., 2003; Van Goethem et al., 2003a; Lamantea and Zeviani, 2004; Mancuso et al., 2004a; Gonzalez-Vioque et al., 2006; Pagnamenta et al., 2006). Polymerase g exhibits a polymerase region and an exonu-clease (proof-reading) region. Most dominant mutations are located in the polymerase region while recessive mutations have been identified mainly in the exonuclease and linker regions. In several families with adPEO, parkinsonism was shown to segregate with the POLG1

mutation (Luoma et al., 2004). Recently POLG1 mutations have been proposed to be associated with various neurological diseases also without PEO. These include Alpers syndrome (Naviaux and Nguyen, 2004; Ferrari et al., 2005; Kollberg et al., 2006), sensory ataxic neuropathy, combined with variable features of CNS involvement (Van Goethem et al., 2004) and parkinsonism (Davidzon et al., 2006). In these conditions mitochondri-al myopathy was not always found and multiple mtDNA deletions were not always present in muscle. However, mtDNA depletion was demonstrated in some cases (Kollberg et al., 2006). A mutation in mtDNA polymer-ase g (PolgA) in the mouse results in multiple somatic mtDNA mutations and a premature-aging phenotype (Trifunovic et al., 2004). This finding indicates that somatic mtDNA mutations are one important cause of aging.

Mitochondrial neurogastrointestinal encephalomyo-pathy (MNGIE) is caused by mutations in the thymidine phosphorylase (TP) gene (ECGF1; Nishino et al., 1999; 2000). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mtDNA including depletion, deletions, and point mutations (Marti et al., 2003; Nishi-gaki et al., 2003a; Marti et al., 2004).

Severe mtDNA depletion syndromes (MDDS) usually present in infancy but may appear later in childhood (Barthelemy et al., 2001). Several genes have been identified: the deoxyguanosine kinase gene (DGUOK), which is associated with hepatic failure and encephalopathy (Mandel et al., 2001b; Taanman et al., 2002; Mancuso et al., 2005; Tadiboyina et al., 2005; Wang et al., 2005) and the thymidine kinase-2 gene (TK2) associated with severe myopathy (Saada et al., 2001; Carrozzo et al., 2003; Mancuso et al., 2003b; Tulinius et al., 2005; Wang et al., 2005). In one report the mtDNA depletion associated with TK2 mutations was reversible (Vila et al., 2003). Two additional genes associated with severe infantile mtDNA depletion have been identified. A homozygous mutation in SUCLA2, which encodes the beta subunit of the ADP-forming succinyl-CoA synthe-tase ligase, was associated with mtDNA depletion, encephalopathy, muscle hypotonia and hearing loss (Elpeleg et al., 2005). Mutations in MPV17, which encodes an inner mitochondrial membrane protein, were associated with mtDNA depletion, encephalopathy and liver failure (Spinazzola et al., 2006). Mutations in POLG1 (see above) are associated with mtDNA depletion as well as multiple mtDNA deletions. In this context it is also of interest that depletion/multiple deletions of mtDNA and mitochondrial myopathy may also be induced by treatment with the nucleoside reverse transcriptase inhibitors (Chariot et al., 1999; Maagaard et al., 2006).

In Amish microcephaly (MCPHA) the mitochondri-al deoxynucleotide carrier (SLC25A19) is mutated (Rosenberg et al., 2002). It was proposed that insufficient transport of dNTPs into mitochondria may interfere with synthesis of mtDNA and cause abnormal brain growth.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook

Post a comment