Increased risk for cardiorespiratory failure associated with the A3302G mutation in the mitochondrial DNA encoded tRNA^Leu(UUR) gene

Abstract

Screening the mitochondrial DNA of a 64-year-old woman with mitochondrial myopathy revealed 76% of the tRNA^Leu(UUR) A3302G mutation in muscle. Muscle of her affected son carried 96% mutated mitochondrial DNA. Both patients were biopsied twice, showing isolated complex I deficiency in the son's first biopsy, additional increased (within normal range) complex II+III activities in his second biopsy, combined complex I, II+III deficiency in mothers first biopsy and additional complex IV deficiency in her second biopsy. After a stay in the mountains, the son died of cardiac arrhythmia. The A3302G mutation has been reported before and is associated with mitochondrial myopathy and cardiorespiratory failure. Pathogenesis is explained by abnormal mtRNA processing, which was also reported for the adjacent C3303T mutation associated with cardiomyopathy and/or skeletal myopathy. Our findings suggest that a high mutation load of the A3302G mutation can lead to fatal cardiorespiratory failure, likely triggered by low environmental oxygen pressure and exercise.

Introduction

The process of oxidative phosphorylation (OXPHOS) for cellular energy production is an important function of mitochondria. Pathogenic mutations in the mitochondrial DNA (mtDNA) as well as mutations in nuclear genes can cause a clinical phenotype of an OXPHOS disorder. Mutations in the mtDNA include point mutations, mainly single nucleotide substitutions, and large rearrangements [1]. Although point mutations can be found throughout the mitochondrial genome, the vast majority of these mutations affects the tRNA genes. Mutations in different tRNA genes and even mutations affecting the same tRNA can cause distinct clinical and biochemical phenotypes [2], [3], [4], [5], [6], [7], [8].

The tRNA^Leu(UUR) gene, in which 18 mutations have been described, is a known ‘hot spot’ for pathogenic mutations [1], [9]. The predominant clinical manifestation is the MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) syndrome, of which the A3243G mutation is the most frequent cause. This same mutation can also lead to diabetes mellitus and deafness, hypertrophic cardiomyopathy, ophthalmoplegia and renal failure [10], [11], [12], [13]. Other base substitutions associated with MELAS are A3252G, T3271C, and T3291C, whereas the C3303T and A3260G mutations both result in hypertrophic cardiomyopathy and myopathy with pediatric onset for the former and adult onset for the latter mutation [14], [15]. Clinical severity and heterogeneity can partly be explained by the mutation percentage. Lower percentages of the A3243G mutation in muscle are for example associated with milder symptoms such as diabetes mellitus and deafness [16], [17]. Another possibility is that the mtDNA background (haplogroup) contributes to the phenotypic expression of the mutation [18]. However, a recent study investigating the phenotypic presentation of the A3243G mutation in 35 patients showed no association between clinical symptoms and haplogroup [7]. It is therefore likely that the clinical manifestation will also be influenced by nuclear genes, ageing and environmental factors [7], although extensive experimental proof is currently unavailable [1], [19].

In this article, we describe a family carrying the tRNA^Leu(UUR) A3302G mutation, in which one patient died of cardiac arrhythmia. The A3302G mutation in tRNA^Leu(UUR) has previously been described in a patient with a mitochondrial myopathy with a profound complex I deficiency caused by abnormal mitochondrial RNA processing. This patient and three family members died of cardiorespiratory problems [20], [21]. A possible relationship between this mitochondrial tRNA mutation and the phenotype of the disease will be discussed.