Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders

Abstract

BackgroundMitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5–40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known.MethodsWe analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both heteroplasmic and homoplasmic variants were identified using two complementary strategies (Surveyor and MitoChip). Multiple correspondence analyses followed by hierarchical ascendant cluster process were used to explore relationships between clinical spectrum, age at onset and localisation of mutations.Results7.4% of deleterious mutations and 22.4% of novel putative mutations were identified. Pathogenic heteroplasmic mutations were more frequent than homoplasmic mutations (4.6% vs 2.8%). Patients carrying deleterious mutations showed symptoms before 16 years of age in 67% of cases. Early onset disease (<1 year) was significantly associated with mutations in protein coding genes (mainly in complex I) while late onset disorders (>16 years) were associated with mutations in tRNA genes. MTND5 and MTND6 genes were identified as ‘hotspots’ of mutations, with Leigh syndrome accounting for the large majority of associated phenotypes.ConclusionsRare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency. This study shows that a comprehensive analysis of mtDNA is essential, and should include young children, for an accurate diagnosis that is now accessible with the development of next generation sequencing technology.

Cell-free DNA in the urine of rats exposed to ionizing radiation

“…It can be seen that in all cases, most heteroduplexes are not digested by this nuclease. However, some of the heteroduplexes were subjected to cleavage, thus indicating the presence of mismatched bases at the Surveyor nuclease cleavage sites (Bannwarth et al 2006(Bannwarth et al , 2013. Reactions were set up with DNA samples isolated from the urine of different rats before their irradiation Fig.…”

“…Surveyor Nuclease assay for mtDNA mismatches is a much faster, more sensitive, and easier procedure to be performed than other ones ''traditionally'' mutation detection (Bannwarth et al 2006(Bannwarth et al , 2013.…”

“…To determine the levels of heteroplasmy of cf-mtDNA isolated from rat urine, we used Surveyor Ò Mutation Detection Kit (Transgenomic, Omaha, NE, USA), as described (Bannwarth et al 2006(Bannwarth et al , 2013Abdullaev et al 2009). Surveyor Nuclease assay for mtDNA mismatches is a much faster, more sensitive, and easier procedure to be performed than other ones ''traditionally'' mutation detection (Bannwarth et al 2006(Bannwarth et al , 2013.…”

Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications

“…A streamlined bioinformatic analysis is necessary to rapidly identify disease-causing mutations. Bioinformatic approaches are also required to identify the mitochondrial DNA heteroplasmy as well as the underlying mitochondrial DNA haplogroup that can impact the disease pathogenicity (Bannwarth et al 2013). Another benefit of the gene panel approach is the opportunity to discover combinations of disease-causing mutations that may be overlooked using sequential screening.…”

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“…Inherited mutations of mtDNA cause insulin resistance and diabetes mellitus in patients [50,51], indicating that mitochondrial dysfunction can be a causative determinant of insulin resistance. Despite this, inherited pathogenic mtDNA mutations do not occur frequently enough (1 in 5,000-10,000 individuals [52,53] to explain the rapidly-expanding prevalence of Type 2 diabetes worldwide. However, the emergence of cytokine-mediated inflammation as a causative mechanism of Type 2 diabetes suggests that cytokine-mediated damage to mitochondria plays a major role in the pathogenesis of diabetes and co-morbid conditions.…”