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1.
Artigo em Inglês | MEDLINE | ID: mdl-31628455

RESUMO

OBJECTIVE: To investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle. DESIGN, SETTING, AND PATIENTS: Glycogenin-1 and glycogenin-2 expression was analyzed by western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency. RESULTS: Both glycogenin-1 and glycogenin-2 were found to be expressed in liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, non-functional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 co-localized with the storage of glycogen and polyglucosan in cardiomyocytes. CONCLUSIONS: Glycogen can be synthesised in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy.

2.
J Clin Neurosci ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31540860

RESUMO

PURPOSE: Transorbital sonography easily detects papilledema and enlarged optic nerve sheath diameters (ONSD) in IIH (idiopathic intracranial hypertension) patients. As the central retinal artery is located within the optic nerve, its hemodynamic properties might be affected by the increased pressure. In this study we assessed the diagnostic usefulness of transorbital sonography in IIH with a special focus on color Doppler imaging of the central retinal artery. IIH patients presented papilledema and enlarged ONSD. ONSD accurately predicted an increased intracranial pressure in IIH (cut-off: 5.8 mm, 81% sensitivity, 80% specificity). 24 h following therapeutic lumbar puncture ONSD diminished significantly, whereas papilledema was not changed. PSV (peak systolic velocity) and Vmean (mean flow velocity) of the central retinal artery were increased in IIH patients compared to controls. PSV accurately predicted an increase of intracranial pressure (cut-off: 11.0 cm/s, 70% sensitivity, 69% specificity). PI (pulsatility index), PSV and Vmean decreased following lumbar puncture. PSV and Vmean decreases were statistically significant for right eyes only in which the values changed to normal. In summary, besides ONSD enlargement and papilledema transbulbar sonography demonstrated an alteration of central retinal artery blood flow in IIH patients. Especially PSV might serve as valuable surrogate marker for intracranial pressure in IIH. Furthermore, the change of intra-individual central retinal arteries PI might be a valuable parameter to demonstrate response to lumbar puncture in IIH patients.

5.
Neuromuscul Disord ; 29(5): 358-367, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30962064

RESUMO

Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNAAsn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ±â€¯4.6%; skeletal muscle 87.8 %±â€¯5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ±â€¯3%; skeletal muscle 74% ±â€¯4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO.

6.
PLoS One ; 14(3): e0213381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845252

RESUMO

OBJECTIVES: The aim of this study was to examine the natural history of brain involvement in adult-onset myotonic dystrophies type 1 and 2 (DM1, DM2). METHODS: We conducted a longitudinal observational study to examine functional and structural cerebral changes in myotonic dystrophies. We enrolled 16 adult-onset DM1 patients, 16 DM2 patients, and 17 controls. At baseline and after 5.5 ± 0.4 years participants underwent neurological, neuropsychological, and 3T-brain MRI examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps (baseline-follow-up in each participant) to focus on disease-related effects over time. RESULTS: We found minor neuropsychological deficits with mild progression in DM1 more than DM2. Daytime sleepiness was restricted to DM1, whereas fatigue was present in both disease entities and stable over time. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up. In DM2, white matter reduction was of lesser extent, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Intriguingly, longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls. CONCLUSION: The lack of significant disease-related progression of gray and white matter involvement over a period of five years in our cohort of DM1 and DM2 patients suggests either a rather slowly progressive process or even a stable course of cerebral changes in middle-aged adult-onset patients. Being the first longitudinal neuroimaging trial in DM1 and DM2, this study provides useful additional information regarding the natural history of brain involvement.

8.
Front Neurol ; 9: 646, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186217

RESUMO

Neuroimaging in myotonic dystrophies provided a major contribution to the insight into brain involvement which is highly prevalent in these multisystemic disorders. Particular in Myotonic Dystrophy Type 1, conventional MRI first revealed hyperintense white matter lesions, predominantly localized in the anterior temporal lobe. Brain atrophy and ventricle enlargement were additional early findings already described almost 30 years ago. Since then, more advanced and sophisticated imaging methods have been applied in Myotonic Dystrophy Types 1 and 2. Involvement of actually normal appearing white matter and widespread cortical affection in PET studies were key results toward the recognition of diffuse and not only focally localized brain pathology in vivo. Later, structural abnormalities of both, gray and white matter, have been found in both forms of the disorder, albeit more prominent in myotonic dystrophy type 1. In Type 1, a consistent widespread cortical and subcortical involvement of gray and white matter affecting all lobes, brainstem and cerebellum was observed. Spectroscopy studies gave additional evidence of neuronal and glial damage in both types. Central questions regarding the origin and spatiotemporal evolution of the CNS involvement and its relevance for clinical symptoms had already been raised 30 years ago, however are still not answered. Results of correlation analyses between neuroimaging and clinical parameters are diverse and with few exceptions not well reproducible across studies. It may be related to the fact that most of the reported studies included only small numbers of subjects, sometimes even not separating Myotonic Dystrophy Type 1 from Type 2. But this heterogeneity may also support the current point of view that the clinical impairments are not simply linked to specific and regionally circumscribed structural or functional brain alterations. It seems more convincing that disturbed networks build the functional and structural substrate of clinical symptoms in these disorders as it is proposed in other neuropsychiatric diseases. Consecutively, structural and functional network analyses may provide additional information regarding the link between brain pathology and clinical symptoms. Up to now, only cross-sectional neuroimaging studies have been published. To analyze the temporal evolution of brain affection, longitudinal studies are urgently needed, and systematic natural history data would be useful to identify potential biomarkers for therapeutic studies.

9.
Biochem Biophys Res Commun ; 503(4): 2770-2777, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30100055

RESUMO

Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology.

10.
J Clin Invest ; 128(3): 1164-1177, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29457785

RESUMO

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.

11.
Audiol Neurootol ; 22(1): 30-40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28601886

RESUMO

BACKGROUND: Auditory synaptopathy/neuropathy (AS/AN) is a heterogeneous disorder, which may be caused by environmental factors like postnatal hyperbilirubinemia or by genetic factors. The genetic forms are subdivided into syndromic and non-syndromic types, and show different inheritance patterns with a strong preponderance of autosomal-recessive forms. To date, only a single locus for non-syndromic autosomal-dominant AS/AN (AUNA1) has been reported in a single family, in which a non-coding DIAPH3 mutation was subsequently described as causative. MATERIALS AND METHODS: Here, we report detailed clinical data on a large German AS/AN family with slowly progressive postlingual hearing loss. Affected family members developed their first symptoms in their second decade. Moderate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members. Comprehensive audiological and neurological tests were performed in the affected family members. Genetic testing comprised linkage analyses with polymorphic markers and a genome-wide linkage analysis using the Affymetrix GeneChip® Human Mapping 250K. RESULTS AND CONCLUSION: We identified a large family with autosomal-dominant AS/AN. By means of linkage analyses, the AUNA1 locus was excluded, and putatively linked regions on chromosomal bands 12q24 and 13q34 were identified as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2). AUNA2 is associated with a slowly progressive postlingual hearing loss without any evidence for additional symptoms in other organ systems.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 13/genética , Nervo Coclear/fisiopatologia , Perda Auditiva Central/genética , Linhagem , Doenças do Nervo Vestibulococlear/genética , Adolescente , Adulto , Idoso , Audiometria de Resposta Evocada , Audiometria de Tons Puros , Criança , Progressão da Doença , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Ligação Genética , Alemanha , Perda Auditiva Central/fisiopatologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doenças do Nervo Vestibulococlear/fisiopatologia
14.
Acta Neuropathol ; 132(3): 453-73, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27393313

RESUMO

Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive. To address this issue for protein aggregate myopathies, we performed a comprehensive, multi-level analysis of mitochondrial pathology in skeletal muscles of human patients with mutations in the intermediate filament protein desmin and in muscles of hetero- and homozygous knock-in mice carrying the R349P desmin mutation. We demonstrate that the expression of mutant desmin causes disruption of the extrasarcomeric desmin cytoskeleton and extensive mitochondrial abnormalities regarding subcellular distribution, number and shape. At the molecular level, we uncovered changes in the abundancy and assembly of the respiratory chain complexes and supercomplexes. In addition, we revealed a marked reduction of mtDNA- and nuclear DNA-encoded mitochondrial proteins in parallel with large-scale deletions in mtDNA and reduced mtDNA copy numbers. Hence, our data demonstrate that the expression of mutant desmin causes multi-level damage of mitochondria already in early stages of desminopathies.


Assuntos
Desmina/genética , Filamentos Intermediários/patologia , Mitocôndrias/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/genética , Animais , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Desmina/metabolismo , Humanos , Filamentos Intermediários/genética , Camundongos Transgênicos , Mitocôndrias/patologia , Doenças Musculares/patologia , Mutação/genética
15.
Acta Neuropathol Commun ; 4(1): 44, 2016 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-27121971

RESUMO

Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.


Assuntos
Epidermólise Bolhosa Simples/genética , Epidermólise Bolhosa Simples/metabolismo , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Mutação , Plectina/genética , Plectina/metabolismo , Adulto , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Epidermólise Bolhosa Simples/patologia , Feminino , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Adulto Jovem
16.
J Neurol ; 263(5): 961-972, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26995359

RESUMO

The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6-48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.


Assuntos
Síndrome MERRF/genética , Síndrome MERRF/fisiopatologia , Mutação , RNA de Transferência de Lisina/genética , RNA/genética , Adolescente , Adulto , Idade de Início , Idoso , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Síndrome MERRF/tratamento farmacológico , Síndrome MERRF/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , RNA Mitocondrial , Sistema de Registros
17.
Brain ; 139(Pt 2): 338-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26685157

RESUMO

Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c.845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/genética , Epilepsia/diagnóstico , Epilepsia/genética , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Subunidades Proteicas/genética , Criança , Complexo IV da Cadeia de Transporte de Elétrons/fisiologia , Epilepsia/complicações , Evolução Fatal , Feminino , Humanos , Doença de Leigh/complicações , Mutação/genética
18.
Ann Neurol ; 76(6): 891-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25272951

RESUMO

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.


Assuntos
Glucosiltransferases/deficiência , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/metabolismo , Glicoproteínas/deficiência , Músculo Esquelético/metabolismo , Adulto , Idoso , Feminino , Glucosiltransferases/genética , Doença de Depósito de Glicogênio/genética , Glicogênio Sintase/metabolismo , Glicoproteínas/genética , Humanos , Masculino , Pessoa de Meia-Idade
19.
JIMD Rep ; 17: 53-61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25155777

RESUMO

OBJECTIVE: To determine the frequency and impact of gastrointestinal symptoms, and bowel and urinary incontinence, as this is currently unknown in adults with Pompe disease. METHODS: Adult German Pompe patients and age- and gender-matched controls were asked about symptoms in the upper and lower intestinal tract as well as urinary incontinence using the Gastrointestinal Symptoms Questionnaire and the International Consultation on Incontinence Questionnaires for Bowel Symptoms and Urinary Incontinence. RESULTS: The overall response rate was 78%; 57 patients and 57 controls participated. The mean age of the patients was 48.3 years ±14.7 (28 female, 29 male). 84% of patients were receiving enzyme replacement therapy. Stool urgency, diarrhoea, and urinary urge incontinence were reported significantly more frequently in patients compared to the age- and gender-matched controls (55%, 56%, 33% vs. 20%, 18%, 7%). 20% of Pompe patients used loperamide daily against diarrhoea. No other gastrointestinal tract-related symptoms were reported to occur more frequently in Pompe patients than in controls. CONCLUSIONS: Compared to age- and gender-matched controls, both urinary and bowel incontinence occur in a higher frequency in adults with Pompe disease and have a major impact on daily life.

20.
Hum Mol Genet ; 23(23): 6147-62, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24986917

RESUMO

MGME1, also known as Ddk1 or C20orf72, is a mitochondrial exonuclease found to be involved in the processing of mitochondrial DNA (mtDNA) during replication. Here, we present detailed insights on the role of MGME1 in mtDNA maintenance. Upon loss of MGME1, elongated 7S DNA species accumulate owing to incomplete processing of 5' ends. Moreover, an 11-kb linear mtDNA fragment spanning the entire major arc of the mitochondrial genome is generated. In contrast to control cells, where linear mtDNA molecules are detectable only after nuclease S1 treatment, the 11-kb fragment persists in MGME1-deficient cells. In parallel, we observed characteristic mtDNA duplications in the absence of MGME1. The fact that the breakpoints of these mtDNA rearrangements do not correspond to either classical deletions or the ends of the linear 11-kb fragment points to a role of MGME1 in processing mtDNA ends, possibly enabling their repair by homologous recombination. In agreement with its functional involvement in mtDNA maintenance, we show that MGME1 interacts with the mitochondrial replicase PolgA, suggesting that it is a constituent of the mitochondrial replisome, to which it provides an additional exonuclease activity. Thus, our results support the viewpoint that MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.


Assuntos
Replicação do DNA , DNA Mitocondrial/genética , Exodesoxirribonucleases/genética , Rearranjo Gênico , Doenças Mitocondriais/genética , Linhagem Celular , Polimerase do DNA Mitocondrial , DNA Mitocondrial/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Exodesoxirribonucleases/metabolismo , Humanos , Doenças Mitocondriais/enzimologia , Mutação
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