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Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases.

ABSTRACT: Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make the exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mtDNA mutations in 61 Korean unrelated families (or isolated patients) with MELAS or MERRF. In particular, the mtDNA sequences were completely determined for 49 patients. From the mutational analysis of mtDNA obtained from blood, 5 confirmed pathogenic mutations were identified in 17 families, and 4 unreported pathogenically suspected mutations were identified in 4 families. The m.3243A>G in the tRNA(Leu(UUR))was predominantly observed in 10 MELAS families, and followed by m.8344A>G in the tRNA(Lys) of 4 MERRF families. Most pathogenic mutations showed heteroplasmy, and the rates were considerably different within the familial members. Patients with a higher rate of mutations showed a tendency of having more severe clinical phenotypes, but not in all cases. This study will be helpful for the molecular diagnosis of mitochondrial diseases, as well as establishment of mtDNA database in Koreans.

SUBMITTER: Choi BO

PROVIDER: S-EPMC2892598 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases.

Choi Byung-Ok BO Hwang Jung Hee JH Cho Eun Min EM Jeong Eun Hye EH Hyun Young Se YS Jeon Hyeon Jeong HJ Seong Ki Min KM Cho Nam Soo NS Chung Ki Wha KW

Experimental & molecular medicine 20100601 6

Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make the exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mtDNA mutations in 61 Korean unrelated families (or isolated patients) with MELAS or MERRF. In particular, the mtDNA sequences were completely determined for 49 patients. From the mutational analysis of mtDNA obtained from blood, 5 confirmed pathogenic mutations were identified in 17 families, and 4 unrepo ...[more]

PMID: 20440095

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Project description:Mitochondrial diseases are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). Normal mitochondrial physiology is responsible, in part, for the aging process itself, as free radical production within the mitochondria results in a lifetime burden of oxidative damage to DNA, especially the mitochondrial DNA that, in turn, replicate the mutational burden in future copies of itself, and lipid membranes. Primary mitochondrial diseases are those caused by mutations in genes that encode for mitochondrial structural and enzymatic proteins, and those proteins required for mitochondrial assembly and maintenance. A number of common adult maladies are associated with defective mitochondrial energy production and function, including diabetes, obesity, hyperthyroidism, hypothyroidism, and hyperlipidemia. Mitochondrial dysfunction has been demonstrated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and some cancers. Polymorphisms in mitochondrial DNA have been linked to disease susceptibility, including death from sepsis and survival after head injury. There is considerable overlap in symptoms caused by primary mitochondrial diseases and those illnesses that affect mitochondrial function, but are not caused by primary mutations, as well as disorders that mimic mitochondrial diseases, but are caused by other identified mutations. Evaluation of these disorders is complex, expensive, and not without false-negative and false-positive results that can mislead the physician. Most of the common heritable mitochondrial disorders have been well-described in the literature, but can be overlooked by many clinicians if they are uneducated about these disorders. In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognized the phenotype and orders appropriate confirmatory testing. However, the majority of patients referred for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing. This article provides introductory comments on mitochondrial structure, physiology, and genetics, but will focus on the presentation and evaluation of adults with mitochondrial symptoms, but who may not have a primary mitochondrial disease.

Project description:We present an autopsied case with A8344G-mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) overlap syndrome accompanied by stroke-like episodes localized to the precentral gyrus. A 16-year-old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho-logically, multifocal laminar necrosis, which is responsible for stroke-like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti-mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)-reactive blood vessels were also noted. Stroke-like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke-like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G-mutated MERRF/MELAS overlap syndrome.

Project description:IntroductionPolycystic Ovarian Syndrome (PCOS) is a globally prevalent condition that leads to infertility in women. While environmental factors contribute to PCOS, maternal genetics also play a significant role. Currently, there is no definitive test for identifying predisposition to PCOS. Hence, our objective is to discover novel maternal genetic risk factors for PCOS by investigating the genomes of patients from Pakistan.MethodsWe utilized Next-Generation Sequencing (NGS) to sequence the complete mitochondrial DNA of three PCOS patients. Subsequently, we employed MitoTIP (Mitochondrial tRNA Informatics Predictor) and PON-mt-tRNA tools to identify variations in the mitochondrial DNA. Our analysis focused on the genes MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB, which displayed common variations in all three genomes. Additionally, we observed individual variations. The D-loop region exhibited the highest frequency of mutations, followed by the non-coding regions of RNR1 and RNR2 genes. Moreover, we detected frameshift mutations in the mitochondrially encoded NADH Dehydrogenase 2 (MT-ND2) and mitochondrially encoded NADH Dehydrogenase 5 (ND5) genes within individual genomes.ResultsOur analysis unveiled six regions with common variations in the mitochondrial DNA of all three PCOS patients. Notably, the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes exhibited these variations. Additionally, we identified individual variations in the mitochondrial DNA. The D-loop region displayed the highest mutation frequency, followed by the non-coding regions of RNR1 and RNR2 genes. Furthermore, frameshift mutations were detected in the MT-ND2 and ND5 genes within individual genomes.ConclusionThrough our study, we have identified variations in mitochondrial DNA that may be associated with the development of PCOS and have the potential to serve as predisposition tests. Our findings highlight the presence of novel mutations in the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes, as well as frameshift mutations in the MT-ND2 and ND5 genes. Pathogenicity analysis indicated that most variants were likely to result in benign cysts. However, the frameshift mutations in the ND2 gene were associated with a high risk of complications and pathogenicity in PCOS. This is the first report identifying these mutations and their association with PCOS, contributing to our understanding of the genetic factors underlying the condition.

Dataset Information

Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases.

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Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases.

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