New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders
نویسندگان
چکیده
OBJECTIVE Mitochondrial respiratory chain disorder (MRCD) is an intractable disease of infants with variable clinical symptoms. Our goal was to identify the causative mutations in MRCD patients. METHODS The subjects were 90 children diagnosed with MRCD by enzyme assay. We analyzed whole mitochondrial DNA (mtDNA) sequences. A cybrid study was performed in two patients. Whole exome sequencing was performed for one of these two patients whose mtDNA variant was confirmed as non-pathogenic. RESULTS Whole mtDNA sequences identified 29 mtDNA variants in 29 patients (13 were previously reported, the other 13 variants and three deletions were novel). The remaining 61 patients had no pathogenic mutations in their mtDNA. Of the 13 patients harboring unreported mtDNA variants, we excluded seven variants by manual curation. Of the remaining six variants, we selected two Leigh syndrome patients whose mitochondrial enzyme activity was decreased in their fibroblasts and performed a cybrid study. We confirmed that m.14439G>A (MT-ND6) was pathogenic, while m.1356A>G (mitochondrial 12S rRNA) was shown to be a non-pathogenic polymorphism. Exome sequencing and a complementation study of the latter patient identified a novel c.55C>T hemizygous missense mutation in the nuclear-encoded gene NDUFA1. INTERPRETATION Our results demonstrate that it is important to perform whole mtDNA sequencing rather than only typing reported mutations. Cybrid assays are also useful to diagnose the pathogenicity of mtDNA variants, and whole exome sequencing is a powerful tool to diagnose nuclear gene mutations as molecular diagnosis can provide a lead to appropriate genetic counseling.
منابع مشابه
Mitochondrial Genetic Variation in Iranian Infertile Men with Varicocele
Objective Several recent studies have shown that mitochondrial DNA mutations lead to major disabilities and premature death in carriers. More than 150 mutations in human mitochondrial DNA (mtDNA) genes have been associated with a wide spectrum of disorders. Varicocele, one of the causes of infertility in men wherein abnormal inflexion and distension of veins of the pampiniform plexus is observe...
متن کاملMitochondrial DNA Mutations, Pathogenicity and Inheritance
Mitochondria contain their own DNA (mtDNA), which codes for 13 proteins (all subunits of the respiratory chain complexes), 22 tRNAs and 2 rRNAs. Several mtDNA point mutations as well as deletions have been shown to be causative in well-defined mitochondrial disorders. A mixture of mutated and wild type mtDNA (heteroplasmy) is found in most of these disorders. Inheritance of mtDNA is maternal, a...
متن کاملRecurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.
Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and ...
متن کاملMixing and matching mitochondrial aminoacyl synthetases and their tRNAs: a new way to treat respiratory chain disorders?
Mutations in mitochondrial DNA are an important cause of human disease and from a therapeutic standpoint, these disorders are currently untreatable. New studies now show that a non‐cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt‐tRNA mutation and that the isolated carboxy‐terminal domain of human mt‐leucyl tRNA synthetase can ameliorate the pa...
متن کاملGene Expression Profiling of Mitochondrial Oxidative Phosphorylation (OXPHOS) Complex I in Friedreich Ataxia (FRDA) Patients
Friedreich ataxia (FRDA) is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein....
متن کامل