Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy

Abstract

The MT-TL1 gene codes for the mitochondrial leucine transfer RNA (tRNA Leu(UUR)) necessary for mitochondrial translation. Pathogenic variants in the MT-TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT-TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNA Leu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient-derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

Clinicopathologic Features of Mitochondrial Nephropathy

“…In this study, we broadly defined mitochondrial nephropathy as nephropathy with at least one of three renal manifestations: proteinuria (≥0.15 g/g Cre), reduced eGFR (<60 mL/min/1.73 m 2 ), and Fanconi syndrome, and with a genetic mutation already confirmed as the cause of MD. Although nephropathy should occur by non-genetic mitochondrial dysfunction as reported by us and others, 19,[25][26][27][28][29] here, we propose that such nephropathy with an acquired mitochondrial dysfunction should not be considered mitochondrial nephropathy, following the definition of mitochondrial disease, mitochondrial encephalopathy, mitochondrial cardiomyopathy, or mitochondrial myopathy [1][2][3][7][8][9][10] .…”

“…Although nephropathy should occur by nongenetic mitochondrial dysfunction as reported by us and others, 18 , 24 , 25 , 26 , 27 , 28 here, we propose that such nephropathy with an acquired mitochondrial dysfunction should not be considered mitochondrial nephropathy, following the definition of MD, mitochondrial encephalopathy, mitochondrial cardiomyopathy, or mitochondrial myopathy. 1 , 2 , 6 , 7 , 8 , 9 …”

“…Mitochondrial encephalopathy, 6 myopathy, 7 cardiomyopathy, 8 , 9 hepatopathy, 10 and deafness 11 are caused by a genetic defect in the OXPHOS function in the cells of each organ. As reported previously, renal diseases with MD include FSGS, tubulointerstitial nephropathy, and Fanconi syndrome caused by proximal tubular dysfunction.…”

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy

“…By far the most frequent manifestation of MIC is nsHCM. As previously discussed, nsHCM is commonly observed in mtDNA-related PMD; however, non-syndromic cases have been reported [ 97 , 98 ]. As an example, the MELAS-associated m.3243A > G variant can present as MIC, having further implications for the affected individual and their biological family (to be discussed below).…”

“…Therefore, low blood heteroplasmy or a negative mtDNA genome analysis may be reconsidered using an alternative tissue type (e.g., urine, muscle). Moreover, the onset of MIC can range from infancy to adulthood, with some forms of infantile disease resulting in early death ( Table 5 ) [ 97 , 108 , 109 ]. Taken together, this makes predicting phenotypes for both an affected individual and an asymptomatic carrier extremely challenging.…”