533 research outputs found
Recommended from our members
Mitochondrial DNA Heteroplasmy and Purifying Selection in the Mammalian Female Germ Line.
Inherited mutations in the mitochondrial (mt)DNA are a major cause of human disease, with approximately 1 in 5000 people affected by one of the hundreds of identified pathogenic mtDNA point mutations or deletions. Due to the severe, and often untreatable, symptoms of many mitochondrial diseases, identifying how these mutations are inherited from one generation to the next has been an area of intense research in recent years. Despite large advances in our understanding of this complex process, many questions remain unanswered, with one of the most hotly debated being whether or not purifying selection acts against pathogenic mutations during germline development
Eye movement recordings to investigate a supranuclear component in chronic progressive external ophthalmoplegia: a cross-sectional study
Background It has been postulated that eye movement disorders in chronic progressive external ophthalmoplegia (CPEO) have a neurological as well as a myopathic component to them.
Aim To investigate whether there is a supranuclear component to eye movement disorders in CPEO using eye movement recordings.
Methods Saccade and smooth pursuit (SP) characteristics together with vestibulo-ocular reflex (VOR) gain and VOR suppression (VORS) gain in 18 patients with CPEO and 34 normal patients were measured using Eyelink II video-oculography.
Results The asymptotic values of the peak velocity main sequence curves were reduced in the CPEO group compared to those of normal patients, with a mean of 161Ā°/s (95% CI 126Ā°/s to 197Ā°/s) compared with 453Ā°/s (95% CI 430 to 475Ā°/s), respectively. Saccadic latency was longer in CPEO (263ā
ms; 95% CI 250 to 278), compared to controls (185ā
ms; 95% CI 181 to 189). Smooth pursuit and VOR gains were impaired in CPEO, although this could be explained by non-supranuclear causes. VORS gain was identical in the two groups.
Conclusions This study does not support a supranuclear component to the ophthalmoplegia of CPEO, although the increased latencies observed may warrant further investigation
Cardiac involvement in hereditary myopathy with early respiratory failure: A cohort study.
OBJECTIVE: To assess whether hereditary myopathy with early respiratory failure (HMERF) due to the c.951434T>C; (p.Cys31712Arg) TTN missense mutation also includes a cardiac phenotype. METHOD: Clinical cohort study of our HMERF cohort using ECG, 2D echocardiogram, and cross-sectional cardiac imaging with MRI or CT. RESULTS: We studied 22 participants with the c.951434T>C; (p.Cys31712Arg) TTN missense mutation. Three were deceased. Cardiac conduction abnormalities were identified in 7/22 (32%): sustained atrioventricular tachycardia (n = 2), atrial fibrillation (n = 2), nonsustained atrial tachycardia (n = 1), premature supraventricular complexes (n = 1), and unexplained sinus bradycardia (n = 1). In addition, 4/22 (18%) had imaging evidence of otherwise unexplained cardiomyopathy. These findings are supported by histopathologic correlation suggestive of myocardial cytoskeletal remodeling. CONCLUSIONS: Coexisting cardiac and skeletal muscle involvement is not uncommon in patients with HMERF arising due to the c.951434T>C; (p.Cys31712Arg) TTN mutation. All patients with pathogenic or putative pathogenic TTN mutations should be offered periodic cardiac surveillance.Wellcome Trust (101876/Z/13/Z, 096919Z/11/Z), Medical Research Council (UK) (G0601943), Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2).This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000306
Water waves generated by a moving bottom
Tsunamis are often generated by a moving sea bottom. This paper deals with
the case where the tsunami source is an earthquake. The linearized water-wave
equations are solved analytically for various sea bottom motions. Numerical
results based on the analytical solutions are shown for the free-surface
profiles, the horizontal and vertical velocities as well as the bottom
pressure.Comment: 41 pages, 13 figures. Accepted for publication in a book: "Tsunami
and Nonlinear Waves", Kundu, Anjan (Editor), Springer 2007, Approx. 325 p.,
170 illus., Hardcover, ISBN: 978-3-540-71255-8, available: May 200
Cell lineage-specific mitochondrial resilience during mammalian organogenesis
Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments
Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance
Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. While dominantly-inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remain challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547Gā>āC variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547Gā>āC variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the nineteenth (19th) locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes
- ā¦