Umeå universitets logga

umu.sePublikationer
Ändra sökning
Avgränsa sökresultatet
1 - 11 av 11
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1.
    Akimoto, Chizuru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Volk, Alexander E.
    van Blitterswijk, Marka
    Van den Broeck, Marleen
    Leblond, Claire S.
    Lumbroso, Serge
    Camu, William
    Neitzel, Birgit
    Onodera, Osamu
    van Rheenen, Wouter
    Pinto, Susana
    Weber, Markus
    Smith, Bradley
    Proven, Melanie
    Talbot, Kevin
    Keagle, Pamela
    Chesi, Alessandra
    Ratti, Antonia
    van der Zee, Julie
    Alstermark, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Calini, Daniela
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Tradowsky, Daniela C.
    Just, Walter
    Daoud, Hussein
    Angerbauer, Sabrina
    DeJesus-Hernandez, Mariely
    Konno, Takuya
    Lloyd-Jani, Anjali
    de Carvalho, Mamede
    Mouzat, Kevin
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Gitler, Aaron D.
    Shaw, Christopher E.
    Rouleau, Guy A.
    van den Berg, Leonard H.
    Van Broeckhoven, Christine
    Rademakers, Rosa
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Kubisch, Christian
    A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories2014Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, nr 6, s. 419-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

  • 2. Müller, Kathrin
    et al.
    Oh, Ki-Wook
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Panthi, Sudhan
    Kim, Seung Hyun
    Nordin, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Freischmidt, Axel
    Ludolph, Albert C.
    Ki, Chang Seok
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Weishaupt, Jochen
    Kim, Young-Eun
    Andersen, Peter Munch
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    De novo mutations in SOD1 are a cause of ALS2022Ingår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 93, s. 201-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.

    Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.

    Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.

    Conclusions:  De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

    Data availability statement: Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

    Ladda ner fulltext (pdf)
    fulltext
  • 3.
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Genetic and functional studies of hereditary myopathy with lactic acidosis2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML, OMIM#255125) is an autosomal recessive disorder which originates from Västerbotten and Ångermanland in the Northern part of Sweden. HML is characterized by severe exercise intolerance which manifests with tachycardia, dyspnea, muscle pain, cramps, elevated lactate and pyruvate levels, weakness and myoglobinuria. The symptoms arise from malfunction of the energy metabolism in skeletal muscles with defects in several important enzymes involved in the TCA cycle and the electron transport chain. All affected proteins contain iron-sulfur (Fe-S) clusters, which led to the suggestion that the disease was caused by malfunctions in either the transportation, assembly or processing of Fe-S clusters.

    The aim of my thesis was to identify the disease causing gene of HML and to investigate the underlying disease-mechanisms. In paper I we identified a disease-critical region on chromosome 12; a region containing 16 genes. One of the genes coded for the Fe-S cluster assembly protein ISCU and an intronic base pair substitution (g.7044G>C) was identified in the last intron of this gene. The mutation gave rise to the insertion of intron sequence into the mRNA, leading to a protein containing 15 abberant amino acids and a premature stop. In paper II we investigated why a mutation in an evolutionary well conserved protein with a very important cellular role, which in addition is expressed in almost all tissues, gives rise to a muscle-restricted phenotype. Semi-quantitative RT-PCR analysis showed that the mutant transcript constituted almost 80% of total ISCU mRNA in muscle, while in both heart and liver the normal splice form was dominant. We could also show that, in mice, complete absence of Iscu protein was coupled with early embryonic death, further emphasizing the importance of the protein in all tissues. These data strongly suggested that tissue-specific splicing was the main mechanism responsible for the muscle-specific phenotype of HML. In paper III the splicing mechanisms that give rise to the mutant ISCU transcript was further investigated. We identified three proteins; PTBP1, IGF2BP1 and RBM39, that could bind to the region containing the mutation and could affect the splicing pattern of ISCU in an in vitro system. PTBP1 repressed the inclusion of the intronic sequence, while IGF2BP1 and RBM39 repressed the total ISCU mRNA level though the effect was more pronounced for the normal transcript. Moreover, IGF2BP1 and RBM39 were also able to reverse the effect of PTBP1. IGF2BP1, though not a splicing factor, had higher affinity for the mutant sequence. This suggested that the mutation enables IGF2BP1 binding, thereby preventing the PTBP1 induced repression seen in the normal case.

    In conclusion, we have determined the genetic cause of HML, identifying a base pair substitution in the last intron of the ISCU gene that gives rise to abnormally spliced transcript. The muscle-specific phenotype was also analyzed and tissue-specific splicing was identified as the main disease-mechanism. Furthermore, nuclear factors with ability to affect the splicing pattern of the mutant ISCU gene were identified. This work has thoroughly investigated the fundamental disease mechanisms, thus providing deeper understanding for this hereditary myopathy.

    Ladda ner fulltext (pdf)
    Angelica Nordin - Genetic and Functional Studies of Hereditary Myopathy with Lactic Acidosis
  • 4.
    Nordin, Angelica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Akimoto, Chizuru
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Alstermark, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Baumann, Peter
    Pinto, Susana
    de Carvalho, Mamede
    Hübers, Annemarie
    Nordin, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Meyer, Thomas
    Grehl, Torsten
    Schweikert, Kathi
    Weber, Markus
    Burkhardt, Christian
    Neuwirth, Christoph
    Holmøy, Trygve
    Morita, Mitsuya
    Tysnes, Ole-Bjørn
    Benatar, Michael
    Wuu, Joanne
    Lange, Dale J.
    Bisgård, Carsten
    Asgari, Nasrin
    Tarvainen, Ilkka
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Neurology, Ulm University, Ulm, Germany.
    Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study2017Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 3-4, s. 256-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.

  • 5.
    Nordin, Angelica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Akimoto, Chizuru
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsukeshi, Tochigi 329-0498, Japan.
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Alstermark, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD2015Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 11, s. 3133-3142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A GGGGCC-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasians. However, little is known about the variability of the GGGGCC expansion in different tissues and whether this correlates with the observed phenotype. Here, we used Southern blotting to estimate the size of hexanucleotide expansions in C9orf72 in neural and non-neural tissues from 18 autopsied ALS and FTD patients with repeat expansion in blood. Digitalization of the Southern blot images allowed comparison of repeat number, smear distribution and expansion band intensity between tissues and between patients. We found marked intra-individual variation of repeat number between tissues, whereas there was less variation within each tissue group. In two patients, the size variation between tissues was extreme, with repeat numbers below 100 in all studied non-neural tissues, whereas expansions in neural tissues were 20-40 times greater and in the same size range observed in neural tissues of the other 16 patients. The expansion pattern in different tissues could not distinguish between diagnostic groups and no correlation was found between expansion size in frontal lobe and occurrence of cognitive impairment. In ALS patients, a less number of repeats in the cerebellum and parietal lobe correlated with earlier age of onset and a larger number of repeats in the parietal lobe correlated with a more rapid progression. In 43 other individuals without repeat expansion in blood, we find that repeat sizes up to 15 are stable, as no size variation between blood, brain and spinal cord was found.

  • 6.
    Nordin, Angelica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Larsson, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be de-repressed by IGF2BP12012Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, nr 3, s. 467-470Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39 and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form.

  • 7.
    Nordin, Angelica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Larsson, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice2011Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 129, nr 4, s. 371-378Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulphur cluster assembly gene (ISCU) leading to incorporation of intron sequence into the mRNA. This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain. The proteins involved in the Fe-S machinery are evolutionary conserved and shown to be fundamental in all organisms examined. ISCU is expressed at high levels in numerous tissues in mammals, including high metabolic tissues like the heart, suggesting that a drastic mutation in the ISCU gene would be damaging to all energy-demanding organs. In spite of this, the symptoms in patients with HML are restricted to skeletal muscle, and it has been proposed that splicing events may contribute to the muscle specificity. In this study we confirm that a striking difference in the splicing pattern of mutant ISCU exists between different tissues. The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart. The splicing differences were also reflected at a functional level, where loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues. We also show that complete loss of ISCU in mice results in early embryonic death. The mice data confirm a fundamental role for ISCU in mammals and further support tissue-specific splicing as the major mechanism limiting the phenotype to skeletal muscle in HML.

  • 8.
    Olsson, Angelica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lind, Lisbet
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect2008Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, nr 11, s. 1666-1672Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.

  • 9.
    Rawcliffe, Denise F. R.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Österman, Lennart
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis2018Ingår i: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 6, nr 6, s. 887-897Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP1 in the regulation of endogenous ISCU mis-splicing.

    Methods: Overexpression and knockdown of PTBP1 was performed in myoblasts from two HML patients and a healthy control. Quantification of ISCU mis-splicing was done by qRTPCR. Biotinylated ISCU RNA, representing wildtype and mutant intron sequence, was used in a pull-down assay with nuclear extracts from myoblasts. Levels of PTBP1 in human cell lines and mice tissues were analyzed by qRTPCR and western blot.

    Results: PTBP1 overexpression in HML patient myoblasts resulted in a substantial decrease of ISCU mis-splicing while knockdown of PTBP1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP1 interacts with both the mutant and wild-type ISCU intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU.

    Conclusion: Our results show that PTBP1 acts as a dominant repressor of ISCU mis-splicing. We also show an inverse correlation between the levels of PTBP1 and ISCU mis-splicing, suggesting that the high level of mis-splicing in the skeletal muscle is primarily due to the low levels of PTBP1.

    Ladda ner fulltext (pdf)
    fulltext
  • 10.
    Tazelaar, Gijs H.P.
    et al.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Hop, Paul J.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Seelen, Meinie
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van Vugt, Joke J.F.A.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van Rheenen, Wouter
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Kool, Lindy
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van Eijk, Kristel R.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Gijzen, Marleen
    Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
    Dooijes, Dennis
    Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
    Moisse, Matthieu
    Neurology Department University Hospitals Leuven, Department of Neurosciences and Leuven Brain Institute (LBI) KU Leuven—University of Leuven, Leuven, Belgium; VIB, Center for Brain & Disease Research, Leuven, Belgium.
    Calvo, Andrea
    ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, SC Neurologia 1U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
    Moglia, Cristina
    ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, SC Neurologia 1U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
    Brunetti, Maura
    ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, SC Neurologia 1U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
    Canosa, Antonio
    ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, SC Neurologia 1U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Pardina, Jesus S. Mora
    ALS Unit, Hospital San Rafael, Madrid, Spain.
    Ravits, John
    Department of Neurosciences, University of California at San Diego, CA, La Jolla, United States.
    Al-Chalabi, Ammar
    Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London, United Kingdom; Department of Neurology, King's College Hospital, London, United Kingdom.
    Chio, Adriano
    ALS Centre, “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, SC Neurologia 1U, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
    McLaughlin, Russell L.
    Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
    Hardiman, Orla
    Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland.
    Van Damme, Philip
    Neurology Department University Hospitals Leuven, Department of Neurosciences and Leuven Brain Institute (LBI) KU Leuven—University of Leuven, Leuven, Belgium; VIB, Center for Brain & Disease Research, Leuven, Belgium.
    de Carvalho, Mamede
    Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal; Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
    Neuwirth, Christoph
    Neuromuscular Diseases Unit / ALS Clinic, Kantonsspital St.Gallen, St.Gallen, Switzerland.
    Weber, Markus
    Neuromuscular Diseases Unit / ALS Clinic, Kantonsspital St.Gallen, St.Gallen, Switzerland.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    van den Berg, Leonard H.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Veldink, Jan H.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    van Es, Michael A.
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis2023Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 122, s. 76-87Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.

    Ladda ner fulltext (pdf)
    fulltext
  • 11. van Rheenen, Wouter
    et al.
    van der Spek, Rick A. A.
    Bakker, Mark K.
    van Vugt, Joke J. F. A.
    Hop, Paul J.
    Zwamborn, Ramona A. J.
    de Klein, Niek
    Westra, Harm-Jan
    Bakker, Olivier B.
    Deelen, Patrick
    Shireby, Gemma
    Hannon, Eilis
    Moisse, Matthieu
    Baird, Denis
    Restuadi, Restuadi
    Dolzhenko, Egor
    Dekker, Annelot M.
    Gawor, Klara
    Westeneng, Henk-Jan
    Tazelaar, Gijs H. P.
    van Eijk, Kristel R.
    Kooyman, Maarten
    Byrne, Ross P.
    Doherty, Mark
    Heverin, Mark
    Al Khleifat, Ahmad
    Iacoangeli, Alfredo
    Shatunov, Aleksey
    Ticozzi, Nicola
    Cooper-Knock, Johnathan
    Smith, Bradley N.
    Gromicho, Marta
    Chandran, Siddharthan
    Pal, Suvankar
    Morrison, Karen E.
    Shaw, Pamela J.
    Hardy, John
    Orrell, Richard W.
    Sendtner, Michael
    Meyer, Thomas
    Basak, Nazli
    van der Kooi, Anneke J.
    Ratti, Antonia
    Fogh, Isabella
    Gellera, Cinzia
    Lauria, Giuseppe
    Corti, Stefania
    Cereda, Cristina
    Sproviero, Daisy
    D'Alfonso, Sandra
    Soraru, Gianni
    Siciliano, Gabriele
    Filosto, Massimiliano
    Padovani, Alessandro
    Chio, Adriano
    Calvo, Andrea
    Moglia, Cristina
    Brunetti, Maura
    Canosa, Antonio
    Grassano, Maurizio
    Beghi, Ettore
    Pupillo, Elisabetta
    Logroscino, Giancarlo
    Nefussy, Beatrice
    Osmanovic, Alma
    Nordin, Angelica
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Lerner, Yossef
    Zabari, Michal
    Gotkine, Marc
    Baloh, Robert H.
    Bell, Shaughn
    Vourc'h, Patrick
    Corcia, Philippe
    Couratier, Philippe
    Millecamps, Stephanie
    Meininger, Vincent
    Salachas, Francois
    Mora Pardina, Jesus S.
    Assialioui, Abdelilah
    Rojas-Garcia, Ricardo
    Dion, Patrick A.
    Ross, Jay P.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Brenner, David
    Freischmidt, Axel
    Bensimon, Gilbert
    Brice, Alexis
    Durr, Alexandra
    Payan, Christine A. M.
    Saker-Delye, Safa
    Wood, Nicholas W.
    Topp, Simon
    Rademakers, Rosa
    Tittmann, Lukas
    Lieb, Wolfgang
    Franke, Andre
    Ripke, Stephan
    Braun, Alice
    Kraft, Julia
    Whiteman, David C.
    Olsen, Catherine M.
    Uitterlinden, Andre G.
    Hofman, Albert
    Rietschel, Marcella
    Cichon, Sven
    Nothen, Markus M.
    Amouyel, Philippe
    Comi, Giancarlo
    Riva, Nilo
    Lunetta, Christian
    Gerardi, Francesca
    Cotelli, Maria Sofia
    Rinaldi, Fabrizio
    Chiveri, Luca
    Guaita, Maria Cristina
    Perrone, Patrizia
    Ceroni, Mauro
    Diamanti, Luca
    Ferrarese, Carlo
    Tremolizzo, Lucio
    Delodovici, Maria Luisa
    Bono, Giorgio
    Manera, Umberto
    Vasta, Rosario
    Bombaci, Alessandro
    Casale, Federico
    Fuda, Giuseppe
    Salamone, Paolina
    Iazzolino, Barbara
    Peotta, Laura
    Cugnasco, Paolo
    De Marco, Giovanni
    Torrieri, Maria Claudia
    Palumbo, Francesca
    Gallone, Salvatore
    Barberis, Marco
    Sbaiz, Luca
    Gentile, Salvatore
    Mauro, Alessandro
    Mazzini, Letizia
    De Marchi, Fabiola
    Corrado, Lucia
    Bertolotto, Antonio
    Gionco, Maurizio
    Leotta, Daniela
    Odddenino, Enrico
    Imperiale, Daniele
    Cavallo, Roberto
    Pignatta, Pietro
    De Mattei, Marco
    Geda, Claudio
    Papurello, Diego Maria
    Gusmaroli, Graziano
    Comi, Cristoforo
    Labate, Carmelo
    Ruiz, Luigi
    Ferrandi, Delfina
    Rota, Eugenia
    Aguggia, Marco
    Di Vito, Nicoletta
    Meineri, Piero
    Ghiglione, Paolo
    Launaro, Nicola
    Dotta, Michele
    Di Sapio, Alessia
    Giardini, Guido
    Tiloca, Cinzia
    Peverelli, Silvia
    Taroni, Franco
    Pensato, Viviana
    Castellotti, Barbara
    Comi, Giacomo P.
    Del Bo, Roberto
    Gagliardi, Stella
    Raggi, Flavia
    Simoncini, Costanza
    Lo Gerfo, Annalisa
    Inghilleri, Maurizio
    Ferlini, Alessandra
    Simone, Isabella L.
    Passarella, Bruno
    Guerra, Vito
    Zoccolella, Stefano
    Nozzoli, Cecilia
    Mundi, Ciro
    Leone, Maurizio
    Zarrelli, Michele
    Tamma, Filippo
    Valluzzi, Francesco
    Calabrese, Gianluigi
    Boero, Giovanni
    Rini, Augusto
    Traynor, Bryan J.
    Singleton, Andrew B.
    Mitne Neto, Miguel
    Cauchi, Ruben J.
    Ophoff, Roel A.
    Wiedau-Pazos, Martina
    Lomen-Hoerth, Catherine
    van Deerlin, Vivianna M.
    Grosskreutz, Julian
    Roediger, Annekathrin
    Gaur, Nayana
    Joerk, Alexander
    Barthel, Tabea
    Theele, Erik
    Ilse, Benjamin
    Stubendorff, Beatrice
    Witte, Otto W.
    Steinbach, Robert
    Huebner, Christian A.
    Graff, Caroline
    Brylev, Lev
    Fominykh, Vera
    Demeshonok, Vera
    Ataulina, Anastasia
    Rogelj, Boris
    Koritnik, Blaz
    Zidar, Janez
    Ravnik-Glavac, Metka
    Glavac, Damjan
    Stevic, Zorica
    Drory, Vivian
    Povedano, Monica
    Blair, Ian P.
    Kiernan, Matthew C.
    Benyamin, Beben
    Henderson, Robert D.
    Furlong, Sarah
    Mathers, Susan
    McCombe, Pamela A.
    Needham, Merrilee
    Ngo, Shyuan T.
    Nicholson, Garth A.
    Pamphlett, Roger
    Rowe, Dominic B.
    Steyn, Frederik J.
    Williams, Kelly L.
    Mather, Karen A.
    Sachdev, Perminder S.
    Henders, Anjali K.
    Wallace, Leanne
    de Carvalho, Mamede
    Pinto, Susana
    Petri, Susanne
    Weber, Markus
    Rouleau, Guy A.
    Silani, Vincenzo
    Curtis, Charles J.
    Breen, Gerome
    Glass, Jonathan D.
    Brown, Robert H., Jr.
    Landers, John E.
    Shaw, Christopher E.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Groen, Ewout J. N.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Fan, Dongsheng
    Garton, Fleur C.
    McRae, Allan F.
    Davey Smith, George
    Gaunt, Tom R.
    Eberle, Michael A.
    Mill, Jonathan
    McLaughlin, Russell L.
    Hardiman, Orla
    Kenna, Kevin P.
    Wray, Naomi R.
    Tsai, Ellen
    Runz, Heiko
    Franke, Lude
    Al-Chalabi, Ammar
    Van Damme, Philip
    van den Berg, Leonard H.
    Veldink, Jan H.
    Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology2021Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 53, nr 12, s. 1636-1648Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

    Ladda ner fulltext (pdf)
    fulltext
1 - 11 av 11
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf