A homoplasmic mtDNA variant can influence the phenotype of the pathogenic m.7472Cins MTTS1 mutation: are two mutations better than one?

Abstract

Mutations in mitochondrial tRNA (mt-tRNA) genes are well recognized as a common cause of human disease, exhibiting a significant degree of clinical heterogeneity. While these differences are explicable, in part, by differences in the innate pathogenicity of the mutation, its distribution and abundance, other factors, including nuclear genetic background, mitochondrial DNA (mtDNA) haplotype and additional mtDNA mutations may influence the expression of mt-tRNA mutations. We describe the clinical, biochemical and molecular findings in a family with progressive myopathy, deafness and diabetes and striking respiratory chain abnormalities due to a well-characterized heteroplasmic mt-tRNA mutation in the mt-tRNA(Ser(UCN)) (MTTS1) gene. In addition to the m.7472Cins mutation, all individuals were homoplasmic for another variant, m.7472A > C, affecting the adjacent nucleotide in the mt-tRNA(Ser(UCN)) structure. In addition to available patient tissues, we have analysed transmitochondrial cybrid clones harbouring homoplasmic levels of m.7472A > C and varying levels of the m.7472Cins mutation in an attempt to clarify the precise role of the m.7472A > C transversion in the underlying respiratory chain abnormality. Evidence from both in vivo and in vitro studies demonstrate that the m.7472A > C is able to modify the expression of the m.7472Cins mutation and would suggest that it is not a neutral variant but appears to cause a biochemical defect by itself, confirming that homoplasmic mtDNA variants can modulate the phenotypic expression of pathogenic, heteroplasmic mtDNA mutations.

Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals

“…The m.7472insC variant was first reported in an Italian family by Tiranti et al. () followed by two Italian pedigrees (Fetoni et al., ; Cardaioli et al., ), Dutch pedigrees (Ensink et al., ; Verhoeven et al., ), German pedigrees (Jaksch et al., ; Schuelke et al., ), United Kingdom, French, and North American pedigrees (Pulkes et al., ; Leveque et al., ; Swalwell et al., ). In extended relatives of these families, this variant occurred either in the homoplasmic or heteroplasmic state; the phenotypes varied from prelingual to progressive postlingual hearing loss with or without associated neurological disorders.…”

“…However, in the absence of aminoglycoside antibiotics, the variants in the MT‐RNR1 gene produce the same phenotypes (Prezant et al., ; Shoffner et al., ; Bacino et al., ; Matthijs et al., ; Pandya et al., ; Estivill et al., ; Matsunaga et al., ; Liu et al., ; Zhu et al., ; Shen et al., ). Pathogenic alleles in MT‐TS1 cause nonsyndromic sensorineural hearing loss in the homoplasmic condition or at a high level of heteroplasmy (Sue et al., ; Li et al., ; Leveque et al., ; Swalwell et al., ). Reports suggest that alterations in this gene can cause failure in tRNA metabolism leading to a decrease in the amount of effective tRNAs, which subsequently results in insufficient mitochondrial protein synthesis and respiration defects (Xing et al., ).…”

Metabolic Myopathies: Update 2009

“…9,28,33,[35][36][37][38][39][40][41] For example, patients with the MELAS A3243G gene mutation can present with later adult-onset deafness and diabetes or fatal encephalomyopathy with seizures and stroke-like episodes in infancy. 42 Less than 10% of patients with genetically confirmed MELAS present before the age of 1, whereas 60%-80% are diagnosed by the age of 15.…”

A novel mitochondrial DNA m.7507A>G mutation is only pathogenic at high levels of heteroplasmy

“…The steady-state levels of mt-tRNA Ser(UCN) were assessed in fibroblasts from the unaffected mother and two affected children by high-resolution northern blot analysis as previously described, using probes for mt-tRNA Ser(UCN) and mt-tRNA Leu(UUR) [12]. Equal loading on the 13% denaturing polyacrylamide/urea gel was confirmed with a 5S rRNA probe, generated using primers at nucleotide positions 1-21 (forward) and 121-101 (reverse) of RNA5S17 (accession number NR_023379.1).…”