Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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White matter involvement is recently being realized as a common finding in mitochondrial disorders. It is considered an inherent part of the classical mitochondrial syndromes which are usually associated with alterations in the mitochondrial DNA such as: Leigh disease, Kearns-Sayre syndrome, mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes, mitochondrial neuro-gastro-intestinal encephalomyopathy and Leber's hereditary optic neuropathy. White matter involvement is also described in mitochondrial disorders due to mutations in the nuclear DNA which are transmitted in an autosomal pattern. MRI findings suggestive of a mitochondrial disease are: small cyst-like lesions in abnormal white matter, involvement of both cerebral and cerebellar white matter, and a combination of a leukoencephalopathy with bilateral basal ganglia lesions. The clinical manifestations may be disproportionate to the extent of white matter involvement. Other organs may frequently be involved. The onset is often in infancy with a neurodegenerative course. The finding of a leukoencephalopathy in a patient with a complex neurologic picture and multisystem involvement should prompt a thorough mitochondrial evaluation.
Mol Genet Metab 2005 Feb
PMID:White matter involvement in mitochondrial diseases. 1567 Jul 18

We studied three patients, each harboring a novel mutation at a highly conserved position in a different mitochondrial tRNA gene. The mutation in patient 1 (T5543C) was associated with isolated mitochondrial myopathy, and occurred in the anticodon loop of tRNA(Trp). In patient 2, with mitochondrial myopathy and marked retinopathy, the mutation (G14710A) resulted in an anticodon swap (Glu to Lys) in tRNA(Glu). Patient 3, who manifested mitochondrial encephalomyopathy and moderate retinal dysfunction, harbored a mutation (C3287A) in the TpsiC loop of tRNA(Leu(UUR)). The mutations were heteroplasmic in muscle in all cases, and sporadic in two cases. PCR-RFLP analysis in all patients showed much higher amounts of mutated mtDNA in affected tissue (muscle) than unaffected tissue (blood), and significantly higher levels of mutated mtDNA in cytochrome c oxidase (COX)-negative muscle fibers than in COX-positive fibers, confirming the pathogenicity of these mutations. The mutation was also detected in single hair roots from all three patients, indicating that each mutation must have arisen early in embryonic development or in maternal germ cells. This suggests that individual hair root analyses may reflect a wider tissue distribution of mutated mtDNA than is clinically apparent, and might be useful in predicting prognosis and, perhaps, the risk of transmitting the mutation to offspring. Our data suggest a correlation between clinical phenotype and distribution of mutated mtDNA in muscle versus hair roots. Furthermore, the high threshold for phenotypic expression in single muscle fibers (92-96%) suggests that therapies may only need to increase the percentage of wild-type mtDNA by a small amount to be beneficial.
Mol Genet Metab 2005 Feb
PMID:Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes. 1567 Jul 24

Maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes result from the 3243A>G mitochondrial point mutation. Current methods to detect the presence of the mutation have limited sensitivity and may lead to potential misclassification of patients with low levels of heteroplasmy. Here, we describe development and validation of a rapid real-time polymerase chain reaction (PCR) method for detection and quantification of levels of heteroplasmy in a single assay. Standard curve analysis indicated that the sensitivity of detection was less than 0.1%. Time from sample loading to data analysis was 110 minutes. We tested 293 samples including 23 known positives, 40 known negatives, and 230 samples from patients clinically classified as having type 2 diabetes. All positive samples were correctly detected, and of those samples previously quantified, heteroplasmy levels determined using the real-time assay correlated well (r(2) = 0.88 and 0.93) with results from fluorescently labeled PCR-restriction fragment length polymorphism and pyrosequencing methods. Screening of 230 patients classified as having type 2 diabetes revealed one patient with 0.6% heteroplasmy who had previously tested negative by PCR-restriction fragment length polymorphism. Real-time PCR provides rapid simultaneous detection and quantification of the 3243A>G mutation to a detection limit of less than 0.1%, without post-PCR manipulation.
J Mol Diagn 2006 May
PMID:Rapid and sensitive real-time polymerase chain reaction method for detection and quantification of 3243A>G mitochondrial point mutation. 1664 9

The 3243A>G mutation in the MTTL1 (tRNA(Leu)) gene and the 8344A>G mutation in the MTTK (tRNA(Lys)) gene are the most common mutations found in mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes and myoclonic epilepsy associated with ragged-red fibers, respectively. These mitochondrial DNA mutations are usually detected by conventional polymerase chain reaction followed by restriction enzyme digestion and gel electrophoresis. We developed a LightCycler real-time polymerase chain reaction assay to detect these two mutations based on fluorescence resonance energy transfer technology and melting curve analysis. Primers and fluorescence-labeled hybridization probes were designed so that the sensor probe spans the mutation site. The observed melting temperatures differed in the mutant and wild-type DNA by 9 degrees C for the MTTL1 gene and 6 degrees C for the MTTK gene. This method correctly identified all 10 samples that were 3243A>G mutation-positive, all 4 samples that were 8344A>G mutation-positive, and all 30 samples that were negative for both mutations, as previously identified by traditional gel-based methods. This LightCycler assay is a rapid and reliable technique for molecular diagnosis of these mitochondrial gene mutations.
J Mol Diagn 2006 May
PMID:Detection of common disease-causing mutations in mitochondrial DNA (mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes MTTL1 3243 A>G and myoclonic epilepsy associated with ragged-red fibers MTTK 8344A>G) by real-time polymerase chain reaction. 1664 16

The clinical presentation and the biochemical and molecular genetic findings are described in a 13 year old Chinese boy with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The diagnosis was initially suspected because of the characteristic clinical features and the strong family history of convulsions. Using polymerase chain reaction-restriction enzyme analysis, the heteroplasmic nt3243 A-->G mutation in mtDNA of peripheral blood leucocytes and a muscle sample was demonstrated. The oligosymptomatic relatives were then screened by this method and the degree of heteroplasmy was analysed. This appears to be the first report of a MELAS family in Hong Kong with this described mutation. Molecular genetic techniques are advantageous in the diagnosis of MELAS.
Clin Mol Pathol 1995 Oct
PMID:Diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in a Chinese family by PCR/restriction enzyme analysis. 1669 23

Members of the peroxisome proliferator-activated receptor gamma coactivator (PGC) family are potent inducers of mitochondrial biogenesis. We have tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. We found that the PGC-1alpha and/or PGC-1beta expression improved mitochondrial respiration in cells harboring a complex III or IV deficiency as well as in transmitochondrial cybrids harboring mitochondrial encephalomyopathy lactic acidosis and stroke A3243G tRNA((Leu)UUR) gene mutation. The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous. These results reinforce the concept that increased mitochondrial biogenesis is a promising venue for the treatment of mitochondrial diseases.
Hum Mol Genet 2009 May 15
PMID:PGC-1alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. 1929 90

Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.
Hum Mol Genet 2009 Sep 15
PMID:Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder. 1952 95

Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNA(Leu(UUR)) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNA(Leu(UUR)). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders.
Mol Cell Biol 2010 May
PMID:Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. 2884 73

MTU1 (TRMU) is a mitochondrial enzyme responsible for the 2-thiolation of the wobble U in tRNA(Lys), tRNA(Glu) and tRNA(Gln), a post-transcriptional modification believed to be important for accurate and efficient synthesis of the 13 respiratory chain subunits encoded by mtDNA. Mutations in MTU1 are associated with acute infantile liver failure, and this has been ascribed to a transient lack of cysteine, the sulfur donor for the thiouridylation reaction, resulting in a mitochondrial translation defect during early development. A mutation in tRNA(Lys) that causes myoclonic epilepsy with ragged-red fibers (MERRF) is also reported to prevent modification of the wobble U. Here we show that mitochondrial translation is unaffected in fibroblasts from an MTU1 patient, in which MTU1 is undetectable by immunoblotting, despite the severe reduction in the 2-thiolation of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). The only respiratory chain abnormality that we could observe in these cells was an accumulation of a Complex II assembly intermediate, which, however, did not affect the level of the fully assembled enzyme. The identical phenotype was observed by siRNA-mediated knockdown of MTU1 in HEK 293 cells. Further, the mitochondrial translation deficiencies present in myoblasts from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode and MERRF patients, which are associated with defects in post-transcriptional modification of mitochondrial tRNAs, did not worsen following knockdown of MTU1 in these cells. This study demonstrates that MTU1 is not required for mitochondrial translation at normal steady-state levels of tRNAs, and that it may possess an as yet uncharacterized function in another sulfur-trafficking pathway.
Hum Mol Genet 2011 Dec 01
PMID:The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation. 2189 Apr 97

Mitochondrial complex I (CI) is a multi-subunit enzyme that forms the major entry point of nicotinamide adenine dinucleotide (NADH) electrons into the respiratory chain. Mutations in the NDUFS4 gene, encoding an accessory subunit of this complex, cause a Leigh-like phenotype in humans. To study the nature and penetrance of the CI defect in different tissues, we investigated the role of NDUFS4 in mice with fatal mitochondrial encephalomyopathy, caused by a systemic inactivation of the Ndufs4 gene. We report that the absence of NDUFS4 in different mouse tissues results in decreased activity and stability of CI. This CI instability leads to an increased disconnection of electron influx of the NADH dehydrogenase module from the holo-complex. However, the formation of respiratory supercomplexes still allows formation of active CI in these Ndufs4 knock-out mice. These results reveal the importance of these supramolecular interactions not only for stabilization but also for the assembly of CI, which becomes especially relevant in pathological conditions.
Hum Mol Genet 2012 Jan 01
PMID:Mitochondrial complex III stabilizes complex I in the absence of NDUFS4 to provide partial activity. 2196 99


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