Disease relevance of PEO1

• OBJECTIVE: To screen patients with mitochondrial disease and multiple mtDNA deletions in muscle for mutations in the coding regions of the POLG, PEO1, and SLC25A4 genes [1].
• Mutations in pol gamma are associated with a spectrum of disease phenotypes including autosomal dominant and recessive forms of progressive external ophthalmoplegia, spino-cerebellar ataxia and epilepsy, and Alpers-Huttenlocher hepatocerebral poliodystrophy [2].
• Two patients, one with PEO, exercise intolerance, and gastrointestinal dysmotility and the other with PEO, neuropathy, deafness, and hypogonadism, both had a Pro587Leu change [3].
• RESULTS: Index patients in both families presented with PEO and developed other clinical disease manifestations, such as myopathy and cardiomyopathy (patient 1) and axonal neuropathy, diabetes mellitus, hearing loss, and myopathy (patient 2), later in the course of illness [4].
• In addition, recessive POLG1 mutations are responsible for sensory-atactic neuropathy, dysarthria and ophthalmoplegia (SANDO), juvenile spino-cerebellar ataxia-epilepsy syndrome (SCAE) and Alpers-Huttenlocher hepatopathic poliodystrophy [5].
• None of the substitutions were found in 192 ethnically matched control chromosomes, 108 patients with progressive external ophthalmoplegia, nor 140 cases of sporadic idiopathic Parkinson disease [6].

Psychiatry related information on PEO1

• A woman with PEO and mental retardation had a heterozygous Gly1076Val mutation [3].
• The mutation was identified in three siblings with PEO, one of them additionally suffered from schizoaffective disorder [7].
• Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone [8].
• 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation [9].

High impact information on PEO1

• Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions [10].
• Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins [11].
• Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria [11].
• A naturally occurring in vivo model for a defect in this cross-talk of two physically separate genomes is a human disease, an autosomal dominant progressive external ophthalmoplegia, in which multiple deletions of mtDNA accumulate in the patients' tissues [12].
• Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome [13].

Chemical compound and disease context of PEO1

• Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy [14].
• We have used the human ovarian cancer cell line PEO1 alongside two in-house derived drug resistant variants: PEO1CarboR (8-fold acquired resistance to carboplatin and cisplatin) and the Pgp expressing PEO1TaxR (15-fold acquired resistance to paclitaxel) [15].
• To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks [16].
• Muscle fatigue, lactate, and pyruvate in mitochondrial myopathy with progressive external ophthalmoplegia [17].
• This study describes the dehydration of an ethanol/water azeotrope during evapomeation using polyion complex cross-linked chitosan composite (q-Chito-PEO acid polyion complex/PES composite) membranes, constructed from quaternized chitosan (q-Chito) and poly(ethylene oxydiglycolic acid) (PEO acid) on a porous poly(ether sulfone) (PES) support [18].

Biological context of PEO1

• To shed light on the pathogenic mechanisms leading to these phenotypes, we have introduced in MIP1, the yeast homologue of POLG, two mutations equivalent to the human Y955C and G268A mutations, which are associated with dominant and recessive PEO, respectively [2].
• Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma [3].
• In this case, a novel heterozygous missense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle [4].
• Progressive external ophthalmoplegia (PEO) with secondary accumulation of multiple deletions of mitochondrial DNA (mtDNA) clinically resembles disorders due to primary mutations of mtDNA but follows a Mendelian inheritance pattern [19].
• After analyzing all positional candidate transcripts, we identified two point mutations in the gene C10orf2 encoding Twinkle, a mitochondrial deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice variant Twinky, underlying IOSCA [20].

Anatomical context of PEO1

• The role of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) in the growth modulation of three human ovarian adenocarcinoma cell lines, PEO1, PEO4 and PEO14, has been examined by measuring responses of the cells growing in monolayer culture to exogenous addition of the growth factors [21].
• CONCLUSIONS : A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory-motor neuropathy [22].
• We also found that one novel KLK5 transcript with a short 5'-untranslated region and a novel KLK7 transcript with a long 3'-untranslated region were highly expressed in the ovarian cancer cell lines OVCAR-3 and PEO1, respectively, but were expressed at very low levels in normal ovarian epithelial cells [23].
• The effect of Matrigel, a solubilised tissue basement membrane extract, has been investigated on the tumorigenicity of 3 breast (MCF-7, T47D and MDA.MB.231) and 5 ovarian [PEO1, PEO1 cDDPr, PEO4, PEO14 and OV(hyg)CAR3] carcinoma cell lines [24].
• The more significant coordinated expression was found in muscle from patients with the MELAS, myoclonic epilepsy with ragged red fibers, and chronic progressive external ophthalmoplegia deletion syndromes, with ragged red muscle fibers and mitochondrial paracrystalline inclusions [25].

Associations of PEO1 with chemical compounds

• We report a novel heterozygous C to A transversion at nucleotide 269 in the ANT1 gene in a German family with PEO, predicted to convert a highly conserved alanine at codon 90 to aspartic acid [7].
• Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line [14].
• However, in one cell line at least (PEO1), both TNF alpha and IFN gamma demonstrated a clearly synergistic effect with cisplatin [26].
• In PEO4 and PEO1 cells, proliferation was stimulated by 17beta-estradiol in a dose-dependent manner [27].
• The results show that both the mitochondrial transcription factor TFAM and mitochondrial single-stranded DNA-binding protein colocalize with Twinkle in intramitochondrial foci defined as nucleoids by the specific incorporation of bromodeoxyuridine [28].

Other interactions of PEO1

• Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders [3].
• RESULTS: No mutation was identified in the PEO1 or SLC25A4 genes [1].
• Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans [2].
• The severe neurological phenotype observed in IOSCA, a result of only a single amino acid substitution in Twinkle and Twinky, suggests that these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations [20].
• Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia [29].

Analytical, diagnostic and therapeutic context of PEO1

• Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations [30].
• Cesium sulfate gradient centrifugation was used to more accurately separate and analyze for DNA-incorporated 5-FU metabolites and confirmed that the absolute level of 5-FU in the DNA of the PEO4 cells was markedly decreased (6.5-fold) compared with that of the sensitive PEO1 cell line [14].
• The expression of coxsackievirus-adenovirus receptor (CAR) and the integrins alpha(v)beta3 and alpha(v)beta5 was analyzed quantitatively (flow cytometry) and qualitatively (immunocytochemistry) in five human ovarian cancer cell lines (PEO1, PEO4, PEO14, SKOV-3, and OVCAR-3) and three control cell lines (293, HeLa, and CHO-K1) [27].
• Differential scanning calorimetry (DSC) and electron microscopy were used to study the phase separation of the hydrophobic (PLA) and hydrophilic (PEO) segments in films made of the copolymers and their blends with high-molecular-weight PLA homopolymers [31].
• METHODS: In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET) [32].

References