| 1. |
- Rice, Gillian I, et al.
(författare)
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Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.
- 2017
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Ingår i: Neuropediatrics. - : Georg Thieme Verlag KG. - 1439-1899 .- 0174-304X. ; 48:3, s. 166-184
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
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| 2. |
- Van Haute, L., et al.
(författare)
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
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| 3. |
- Bernhardt, A. M., et al.
(författare)
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A unified classification approach rating clinical utility of protein biomarkers across neurologic diseases
- 2023
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi) genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology. Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 4. |
- Redecke, Lars, et al.
(författare)
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Natively inhibited Trypanosoma brucei cathepsin B structure determined by using an X-ray laser.
- 2013
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 339:6116, s. 227-30
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Tidskriftsartikel (refereegranskat)abstract
- The Trypanosoma brucei cysteine protease cathepsin B (TbCatB), which is involved in host protein degradation, is a promising target to develop new treatments against sleeping sickness, a fatal disease caused by this protozoan parasite. The structure of the mature, active form of TbCatB has so far not provided sufficient information for the design of a safe and specific drug against T. brucei. By combining two recent innovations, in vivo crystallization and serial femtosecond crystallography, we obtained the room-temperature 2.1 angstrom resolution structure of the fully glycosylated precursor complex of TbCatB. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals.
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| 5. |
- Namavar, Yasmin, et al.
(författare)
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Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.
- 2011
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 134:Pt 1, s. 143-56
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Tidskriftsartikel (refereegranskat)abstract
- Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
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| 6. |
- Nienaber, Juhsien J.C., et al.
(författare)
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Methicillin-susceptible staphylococcus aureus endocarditis isolates Are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins
- 2011
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 204, s. 704-713
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Tidskriftsartikel (refereegranskat)abstract
- Background. Using multinational collections of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from infective endocarditis (IE) and soft tissue infections (STIs), we sought to (1) validate the finding that S. aureus in clonal complex (CC) 30 is associated with hematogenous complications and (2) test the hypothesis that specific genetic characteristics in S. aureus are associated with infection severity. Methods. IE and STI isolates from 2 cohorts were frequency matched by geographic origin. Isolates underwent spa typing to infer CC and multiplex polymerase chain reaction for presence of virulence genes. Results. 114 isolate pairs were genotyped. IE isolates were more likely to be CC30 (19.5% vs 6.2%; P = .005) and to contain 3 adhesins (clfB, cna, map/eap; P <.0001 for all) and 5 enterotoxins (tst, sea, sed, see, and sei; P ≤.005 for all). CC30 isolates were more likely to contain cna, tst, sea, see, seg, and chp (P < .05 for all). Conclusions. MSSA IE isolates were significantly more likely to be CC30 and to possess a distinct repertoire of virulence genes than MSSA STI isolates from the same region. The genetic basis of this association requires further study. © The Author 2011.
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| 7. |
- Topuz, G., et al.
(författare)
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Carboniferous high-potassium I-type granitoid magmatism in the Eastern Pontides: The Gumushane pluton (NE Turkey)
- 2010
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Ingår i: Lithos. - 0024-4937. ; 116:1-2, s. 92-110
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Tidskriftsartikel (refereegranskat)abstract
- The Gumushane pluton, a high-K calc-alkaline I-type granodionte/granite complex, forms an important component of the pre-Liassic basement of the Eastern Pontides (NE Turkey) In its eastern part, the pluton shows a compositional zonation ranging from biotite-hornblende granodiorite in the NW through biotite-hornblende granite to leucogranite/granophyre in the SE Numerous mafic microgranular enclaves (up to similar to 40 cm in diameter) suggest the former presence of globules of mafic melt during crystallization Emplacement of the pluton occurred during the latest Early Carboniferous, as shown by the 320 +/- 4 Ma (40)Ar-(39)Ar bionte/homblende and 324 +/- 6 Ma LA-ICP-MS U-Pb zircon ages. In Harker diagrams, samples of the different rock types exhibit well-defined data trends. With increasing SiO(2), the abundances of TiO(2), Al(2)O(3), Fe(2)O(3)(tot), MnO, MgO, CaO, P(2)O(5) and Sc decrease, but those of K(2)O and Rb increase However, the variations of Sr, Ba, (La/Yb)(cn) Sr/Y and Sigma REEs vs SiO(2) form distinctive groupings, which cannot be explained by a simple fractional crystallization Chondrite-normalized (cn) REE patterns of granodionte/granite samples show concave-upward shapes with (La/Yb)(cn) ranging from 5.2 to 124 and Eu/Eu* from 084 to 0.47, while there is almost no fractionation of the middle REE relative to the heavy REE In primitive mantle-normalized element concentration diagrams, all rocks display marked negative anomalies in Ba, Nb/Ta, Sr, P and Ti. but positive anomalies in K and Pb. These geochemical features imply a fractionating mineral assemblage of clinopyroxene, amphibole and plagioclase without significant involvement of garnet. The granophyres are, on the other hand, characterized by higher K(2)O/Na(2)O and Rb/Sr ratios, lower (La/Yb)(cn), ratios (1 3 to 4 8) and more pronounced negative anomalies in Ba, Nb/Ta, Sr, Eu, P and Ti Initial epsilon(Nd) values range from -3 78 to -5.30 and Nd model ages from 1 38 to 163 Ga The magmas of the granite/granodiorite portion were probably generated by partial melting of high-potassic amphibolitic rocks, and those of the granophyres by a relatively felsic micaceous crustal source. The Gumushane pluton was emplaced at the wake of the lowpressure-high-temperature metamorphism, and is regarded as a late phase of Hercynian orogeny in the Eastern Pontides (C) 2010 Elsevier B.V All rights reserved
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| 8. |
- Topuz, G., et al.
(författare)
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Jurassic ophiolite formation and emplacement as backstop to a subduction-accretion complex in northeast Turkey, the Refahıye ophiolite, and relation to the Balkan ophiolites
- 2013
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Ingår i: American Journal of Science. - : American Journal of Science (AJS). - 0002-9599. ; 313:10, s. 1054-1087
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Tidskriftsartikel (refereegranskat)abstract
- The eastern Mediterranean region within the Tethyan realm shows a high concentration of ophiolites with contrasting times of formation and emplacement along the belt: In the Balkans, the ophiolites formed during the early to medial Jurassic, and were obducted during the late Jurassic, whereas in Turkey and farther east, structurally intact Jurassic ophiolites are rare and Jurassic ophiolite obduction is unknown. Here we report a structurally intact, large ophiolite body of early Jurassic age from NE Turkey, the Refahiye ophiolite, located close to the suture zone between the Eastern Pontides and the Menderes-Taurus block. The Refahiye ophiolite forms an outcrop belt, 175 km long and 20 km wide, and is tectonically bound by the late Cretaceous ophiolitic melange to the south, and by the North Anatolian Transform Fault against the Triassic low-grade metamorphic rocks to the north. Early to medial Jurassic very low- to low-grade metamorphic rocks, interpreted as intraoceanic subduction-accretion complexes, occur either beneath the ophiolite or as thrust slices within it. The ophiolite body within the studied section is made up of mantle peridotite (clinopyroxene-bearing harzburgite and minor dunite) crosscut by up to 20 cm thick veins of clinopyroxenite and later dikes/pods/stocks of gabbro ranging in size from 2 m to several hundreds of meters. The gabbro is represented by two distinct types: (i) cumulate gabbro, and (ii) non-cumulate gabbro with locally well-developed igneous foliation. Within the non-cumulate gabbro or enclosing peridotite, there are up to 5 m and 50 cm-thick veins of trondhjemite and pegmatitic gabbro, respectively. LA-ICP-MS dating on zircons from two irondhjemite samples yielded weighted mean ages of similar to 184 +/- 4 Ma and 178 +/- 4 Ma (2 sigma), respectively, suggesting formation during early Jurassic time. Formation in a suprasubduction-zone forearc setting is inferred from (i) wide-ranging pyroxene and spinel compositions in the peridotites as documented in most suprasubduction-zone ophiolites, (ii) arc tholeiitic signature of the non-cumulate gabbros, and (iii) association of the ophiolite with the coeval subduction-accretion complexes. Emplacement of a trapped forearc ophiolite above its own subduction-accretion complex as a backstop is proposed based on a series of field relationships such as (i) intimate association of the unsubducted suprasubduction-zone ophiolite with coeval accretionary complexes, (ii) absence of unambiguous relationship to the southern Atlantic-type continental margin, and (iii) absence of any stratigraphic indications for the ophiolite obduction in the southern Atlantic-type continental margin during Jurassic time. This is a clear difference from the Jurassic ophiolites in the Balkans that were obducted over the Atlantic-type continental margin. This difference in mode of emplacement is most probably related to the greater distance of the intra-oceanic subduction zone to the Atlantic-type continental margin than it was in the Balkans, which is commensurate with the greater width of the Tethys in the east during Jurassic time.
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| 9. |
- Weist, P., et al.
(författare)
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Assessing SNP-markers to study population mixing and ecological adaptation in Baltic cod
- 2019
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Atlantic cod (Gadus morhua) is a species of great ecological and economical importance in the Baltic Sea. Here, two genetically differentiated stocks, the western and the eastern Baltic cod, display substantial mechanical mixing, hampering our understanding of cod ecology and impeding stock assessments and management. Based on whole-genome re-sequencing data from reference samples obtained from the study area, we designed two different panels of Single Nucleotide Polymorphisms markers (SNPs), which take into account the exceptional genome architecture of cod. A minimum panel of 20 diagnostic SNPs and an extended panel (20 diagnostic and 18 biologically informative SNPs, 38 in total) were developed and validated to distinguish unambiguously between the western and the eastern Baltic cod stocks and to enable studies of local adaptation to the specific environment in the Baltic Sea, respectively. We tested both panels on cod sampled from the southern Baltic Sea (n = 603) caught in 2015 and 2016. Genotyping results showed that catches from the mixing zone in the Arkona Sea, were composed of similar proportions of individuals of the western and the eastern stock. Catches from adjacent areas to the east, the Bornholm Basin and Gdansk Deep, were exclusively composed of eastern Baltic cod, whereas catches from adjacent western areas (Belt Sea and Oresund) were composed of western Baltic cod. Interestingly, the two Baltic cod stocks showed strong genetic differences at loci associated with life-history trait candidate genes, highlighting the species' potential for ecological adaptation even at small geographical scales. The minimum and the extended panel of SNP markers presented in this study provide powerful tools for future applications in research and fisheries management to further illuminate the mixing dynamics of cod in the Baltic Sea and to better understand Baltic cod ecology.
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