Fatal manifestation of a de novo ND5 mutation: Insights into the pathogenetic mechanisms of mtDNA ND5 gene defects
Introduction
Complex I deficiencies have been implicated in severe neurological deficiencies in infants and children, as well as late-onset neurodegenerative disorders, such as Parkinson’s disease (PD), with the former being the most often seen within the Leigh syndrome (LS) phenotype (Leigh, 1951). A diagnostically important feature of LS is symmetrical vasculonecrotic lesions, primarily in the brainstem and basal ganglia, although a wide range of other neurological and systemic abnormalities have also been seen (reviewed by Lerman-Sagie et al., 2005).
A variety of both nuclear gene defects and mitochondrial DNA (mtDNA) mutations has being reported in LS patients (Dahl, 1998). From a mitochondrial perspective, point mutations in the gene encoding the ND5 subunit of complex I have been associated with LS, Leber’s hereditary optic neuropathy (LHON), and mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes syndrome (MELAS), as well as overlap mitochondriopathy syndromes (e.g., Taylor et al., 2002, Lebon et al., 2003, Sudo et al., 2004, Mayorov et al., 2005). Thus, the ND5 gene appears to be a mutational hot spot for severe neurodegenerative phenotypes expressing MELAS or LS/LHON/MELAS syndromes (Santorelli et al., 1997, Liolitsa et al., 2003). However, most of these mutations have been described as sporadic genetic defects or single clinical cases, and their association with deleterious phenotypes has yet to be confirmed.
In addition, the expression mechanisms of the reported mutations have not been adequately elucidated. As a result, there is still limited knowledge about ND5 pathogenesis. The association of different mutations with the same syndrome, and different syndromes with the same mutation, has prompted speculation that additional influences such as genetic background or environmental factors may be important contributory determinants of phenotypic expression (Morgan-Hughes and Hanna, 1999). This influence is particularly evident for some mitochondrial disorders (e.g., LHON), which demonstrate strong association with certain ancient polymorphisms in the mtDNA phylogenetic tree (e.g., Wallace et al., 1999).
In this report, we describe the de novo occurrence of a heteroplasmic 12706T → C (12706C) mutation in a patient who clinically manifested fatal LS with an unusual sympathetic imbalance and asymmetric brain lesion. This mutation was previously shown to cause a substantial decrease in Complex I activity in patients with LS-like syndrome (Taylor et al., 2002, Lebon et al., 2003), and has been suggested to play a causative role in idiopathic PD (Parker and Parks, 2005).
Our phylogenetic analysis of current and previously reported 12706C cases demonstrates that all of them occurred in different mtDNA backgrounds through independent mutational events. This aspect of the 12706C mutation supports its pathogenetic significance for LS/MELAS, and points to its having an important role in the expression of neurodegeneration in different families. We also examined deleterious mtDNA mutations previously reported for the ND5 gene, and predict that some of them may share common expression mechanisms that affect functionally important amino acid motifs.
Section snippets
Case report
A girl (case G.) was born in 1996 to healthy unrelated parents after a 44-week pregnancy (weight 3500 g, length 48 cm). As an infant, she was noted to have a mild psychomotor retardation and poor weight gain. At the age of 7, she was admitted to the hospital because of severe deterioration of her metabolic state with reactive sympathic nervous system hyperactivity. This spell was characterized by hypertension (BP: 240/140 mm Hg), sinus tachycardia (P: 160–180/min), hyperglycemia, bulimia,
Clinical profile
The majority of ND5 mutations often result in overlapping neurodegenerative syndromes with profusion of clinical symptoms (e.g., Crimi et al., 2003, Liolitsa et al., 2003), a pattern that likely indicates systemic organ responses to severe genetic defects. A number of symptoms, including hemisphere cortical atrophy, the involvement of basal ganglia, probable brainstem lesion with absence of vital reflexes, and dilated cardiomyopathy, have been repeatedly observed in LS (Leigh, 1951, Morris et
Phylogenetic distribution of the 12706C mutation
The incomplete penetrance and highly varying expression of mitochondriopathies suggests the presence of additional factors in their pathogenesis. There is growing evidence that certain mtDNA environments may influence the expression of common disorders, and that, for some mitochondrial disorders to develop, they may need to interact with mitochondrial DNA environment (Torroni et al., 1997, Wallace et al., 1999, Zhadanov et al., 2006).
The high mutation rate of the mtDNA may disguise the role of
Acknowledgements
We are grateful to our patients for their participation in this study. The authors thank Dr. Ludmila Osipova for providing control population samples. This study was supported by a Fight for Sight Grant-in-Aid and Faculty Research Funds from the University of Pennsylvania to T.G.S.
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