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  • 1.
    Asp, Michaela
    et al.
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Salmen, Fredrik
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Ståhl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Vickovic, Sanja
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Felldin, Ulrika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Navarro, Jose Fernandez
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Maaskola, Jonas
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Eriksson, Maria J.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Physiol, Stockholm, Sweden..
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Corbascio, Matthias
    Karolinska Univ Hosp, Dept Cardiothorac Surg & Anesthesiol, Solna, Sweden..
    Persson, Hans
    Danderyd Hosp, Dept Cardiol, Stockholm, Sweden.;Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Linde, Cecilia
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Lundeberg, Joakim
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Spatial detection of fetal marker genes expressed at low level in adult human heart tissue2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12941Article in journal (Refereed)
    Abstract [en]

    Heart failure is a major health problem linked to poor quality of life and high mortality rates. Hence, novel biomarkers, such as fetal marker genes with low expression levels, could potentially differentiate disease states in order to improve therapy. In many studies on heart failure, cardiac biopsies have been analyzed as uniform pieces of tissue with bulk techniques, but this homogenization approach can mask medically relevant phenotypes occurring only in isolated parts of the tissue. This study examines such spatial variations within and between regions of cardiac biopsies. In contrast to standard RNA sequencing, this approach provides a spatially resolved transcriptome- and tissue-wide perspective of the adult human heart, and enables detection of fetal marker genes expressed by minor subpopulations of cells within the tissue. Analysis of patients with heart failure, with preserved ejection fraction, demonstrated spatially divergent expression of fetal genes in cardiac biopsies.

  • 2. Baltscheffsky, Herrick
    et al.
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    On an Early Gene for Membrane-Integral Inorganic Pyrophosphatase in the Genome of an Apparently Pre-LUCA Extremophile, the Archaeon Candidatus Korarchaeum cryptofilum2014In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 78, no 2, p. 140-147Article in journal (Refereed)
    Abstract [en]

    A gene for membrane-integral inorganic pyrophosphatase (miPPase) was found in the composite genome of the extremophile archaeon Candidatus Korarchaeum cryptofilum (CKc). This korarchaeal genome shows unusual partial similarity to both major archaeal phyla Crenarchaeota and Euryarchaeota. Thus this Korarchaeote might have retained features that represent an ancestral archaeal form, existing before the occurrence of the evolutionary bifurcation into Crenarchaeota and Euryarchaeota. In addition, CKc lacks five genes that are common to early genomes at the LUCA border. These two properties independently suggest a pre-LUCA evolutionary position of this extremophile. Our finding of the miPPase gene in the CKc genome points to a role for the enzyme in the energy conversion of this very early archaeon. The structural features of its miPPase indicate that it can pump protons through membranes. An miPPase from the extremophile bacterium Caldicellulosiruptor saccharolyticus also has a sequence indicating a proton pump. Recent analysis of the three-dimensional structure of the miPPase from Vigna radiata has resulted in the recognition of a strongly acidic substrate (orthophosphate: Pi, pyrophosphate: PPi) binding pocket, containing 11 Asp and one Glu residues. Asp (aspartic acid) is an evolutionarily very early proteinaceous amino acid as compared to the later appearing Glu (glutamic acid). All the Asp residues are conserved in the miPPase of CKc, V. radiata and other miPPases. The high proportion of Asp, as compared to Glu, seems to strengthen our argument that biological energy conversion with binding and activities of orthophosphate (Pi) and energy-rich pyrophosphate (PPi) in connection with the origin and early evolution of life may have started with similar or even more primitive acidic peptide funnels and/or pockets.

  • 3. Barbaro, Michela
    et al.
    Soardi, Fernanda C.
    Ostberg, Linus J.
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    de Mello, Maricilda Palandi
    Wedell, Anna
    Lajic, Svetlana
    In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, p. 37-44Article in journal (Refereed)
    Abstract [en]

    BackgroundA detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). ObjectiveTo investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. Design and patientsThe CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. Main outcome measureTo verify the disease-causing state of novel mutations. ResultsFive CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations.

  • 4.
    Das, Sarbashis
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frisk, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Maria J.
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Walentinsson, Anna
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Dept Thorac Surg, S-17176 Stockholm, Sweden.
    Hage, Camilla
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Kumar, Chanchal
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden;Karolinska Inst, ICMC, Dept Med, S-14157 Huddinge, Sweden.
    Asp, Michaela
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Lundeberg, Joakim
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Maret, Eva
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Persson, Hans
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, S-18288 Stockholm, Sweden;Danderyd Hosp, Dept Cardiol, S-18288 Stockholm, Sweden.
    Linde, Cecilia
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, S-17177 Stockholm, Sweden.
    Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3179Article in journal (Refereed)
    Abstract [en]

    Heart failure affects 2-3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics would show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction >= 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group.

  • 5.
    Ison, Jon
    et al.
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Ienasescu, Hans
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Chmura, Piotr
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
    Rydza, Emil
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
    Menager, Herve
    Inst Pasteur, Hub Bioinformat & Biostat, C3BI USR, 3756 IP CNRS, Paris, France.
    Kalas, Matus
    Univ Bergen, Computat Biol Unit, Dept Informat, N-5020 Bergen, Norway.
    Schwammle, Veit
    Univ Southern Denmark, Dept Biochem & Mol Biol, Campusvej 55, DK-5230 Odense, Denmark;Univ Southern Denmark, VILLUM Ctr Bioanalyt Sci, Campusvej 55, DK-5230 Odense, Denmark.
    Gruening, Bjoern
    Albert Ludwigs Univ Freiburg, Dept Comp Sci, Georges Kohler Allee 106, D-79110 Freiburg, Germany.
    Beard, Niall
    Univ Manchester, Sch Comp Sci, Oxford Rd, Manchester M13 9PL, Lancs, England.
    Lopez, Rodrigo
    EMBL European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England.
    Duvaud, Severine
    SIB Swiss Inst Bioinformat, Quartier Sorge Batiment Amphipole, CH-1015 Lausanne, Switzerland.
    Stockinger, Heinz
    SIB Swiss Inst Bioinformat, Quartier Sorge Batiment Amphipole, CH-1015 Lausanne, Switzerland.
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Varekova, Radka Svobodova
    Masaryk Univ Brno, CEITEC Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Racek, Tomas
    Masaryk Univ Brno, CEITEC Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Vondrasek, Jiri
    Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo Namesti 2, Prague 16000, Czech Republic.
    Peterson, Hedi
    Univ Tartu, Inst Comp Sci, ELIXIR EE, J Liivi 2, Tartu, Estonia.
    Salumets, Ahto
    Univ Tartu, Inst Comp Sci, ELIXIR EE, J Liivi 2, Tartu, Estonia.
    Jonassen, Inge
    Hooft, Rob
    Dutch Techcentre Life Sci, Jaarbeurspl 6, NL-3521 AL Utrecht, Netherlands.
    Nyronen, Tommi
    CSC IT Ctr Sci, POB 405, FI-02101 Espoo, Finland.
    Valencia, Alfonso
    BSC, Barcelona 08034, Spain;ICREA, Pg Lluis Co 23, Barcelona 08010, Spain.
    Capella, Salvador
    BSC, Barcelona 08034, Spain.
    Gelpi, Josep
    BSC, Barcelona 08034, Spain;Univ Barcelona, INB BSC CNS, Dept Biochem & Mol Biomed, Barcelona, Spain.
    Zambelli, Federico
    Natl Res Council CNR, Inst Biomembranes Bioenerget & Mol Biotechnol, Via Amendola 165-A, Bari, Italy;Univ Milan, Dept Biosci, Via Celoria 26, Milan, Italy.
    Savakis, Babis
    Biomed Sci Res Ctr, Alexander Fleming 34 Al Fleming Str, Vari 16672, Greece.
    Leskosek, Brane
    Univ Ljubljana, Fac Med, ELIXIR SI, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia.
    Rapacki, Kristoffer
    Blanchet, Christophe
    CNRS, UMS 3601, Inst Francais Bioinformat, IFB Core, 2 Rue Gaston Cremieux, F-91000 Evry, France.
    Jimenez, Rafael
    ELIXIR Hub, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England.
    Oliveira, Arlindo
    Inst Super Tecn, INESC ID, R Alves Redol 9, Lisbon, Portugal.
    Vriend, Gert
    Radboud Univ Nijmegen, Med Ctr, Postbus 9101, NL-6500 HB Nijmegen, Netherlands.
    Collin, Olivier
    Plateforme GenOuest Univ Rennes, INRIA, CNRS, IRISA, F-35000 Rennes, France.
    van Helden, Jacques
    Aix Marseille Univ, INSERM, Lab Theory & Approaches Genome Complex TAGC, Marseille, France.
    Longreen, Peter
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Brunak, Soren
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark;Tech Univ Denmark, Dept Bio & Hlth Informat, Bldg 208, DK-2800 Lyngby, Denmark.
    The bio.tools registry of software tools and data resources for the life sciences2019In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, no 1, article id 164Article in journal (Refereed)
    Abstract [en]

    Bioinformaticians and biologists rely increasingly upon workflows for the flexible utilization of the many life science tools that are needed to optimally convert data into knowledge. We outline a pan-European enterprise to provide a catalogue () of tools and databases that can be used in these workflows. bio.tools not only lists where to find resources, but also provides a wide variety of practical information.

  • 6.
    Karlsson, Leif
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm, Sweden.
    Michelatto, Debora de Paula
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm, Sweden; Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP, Brazil.
    Gori Lusa, Ana Leticia
    Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP, Brazil.
    Mgnani Silva, Camila D'Almeida
    Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP, Brazil.
    Ostberg, Linus J.
    Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden; Karolinska Inst, Dept Med Biochem & Biophys, eSSENCE, Stockholm, Sweden.
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Guerra-Junior, Gil
    Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP, Brazil.
    Valente de Lemos-Marini, Sofia Helena
    Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP, Brazil.
    Baldazzi, Lilia
    S Orsola Malpighi Univ Hosp, Ctr Rare Endocrine Condit CARENDO BO Endo ERN, Dept Woman Child & Urologkal Dis, Bologna, Italy.
    Menabo, Soara
    S Orsola Malpighi Univ Hosp, Ctr Rare Endocrine Condit CARENDO BO Endo ERN, Dept Woman Child & Urologkal Dis, Bologna, Italy.
    Balsamo, Antonio
    S Orsola Malpighi Univ Hosp, Ctr Rare Endocrine Condit CARENDO BO Endo ERN, Dept Woman Child & Urologkal Dis, Bologna, Italy.
    Greggio, Nella Augusta
    Dept Womens & Childrens Hlth Padua, Pediat Endocrinol Unit, Padua, Italy.
    de Mello, Maricilda Palandi
    Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP, Brazil.
    Barbaro, Michela
    Karolinska Univ Hosp, Ctr Inherited Metab Dis CMMS L7 05, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Lajic, Svetlana
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm, Sweden.
    Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia2019In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 73, p. 50-56Article in journal (Refereed)
    Abstract [en]

    Objective: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH.

    Methods: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed.

    Results: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40–82%). An additive effect on the reduction of enzymatic activity (1–17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro.

    Conclusions: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.

     

  • 7. Norling, Ameli
    et al.
    Hirschberg, Angelica Linden
    Iwarsson, Erik
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wedell, Anna
    Barbaro, Michela
    Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 12, p. 661-668Article in journal (Refereed)
    Abstract [en]

    Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1 M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 genes involved in sex development. Fourteen patients with 46,XY gonadal DSD were enrolled in the study. Nine individuals were analyzed by array CGH. All patients were included in a follow up sequencing study of candidate genes. Three novel candidate regions for 46,XY GD were identified in two patients. An interstitial duplication of the SUPT3H gene and a deletion of C2ORF80 were detected in a pair of affected siblings. Sequence analysis of these genes in all patients revealed no additional mutations. A large duplication highlighting PIP5K1B, PRKACG and FAM189A2 as candidates for 46, XY GD, were also detected. All five genes are expressed in testicular tissues, and one is shown to cause gonadal DSD in mice. However detailed functional information is lacking for these genes.

  • 8. Ostberg, Linus J.
    et al.
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoog, Jan-Olov
    The mammalian alcohol dehydrogenase genome shows several gene duplications and gene losses resulting in a large set of different enzymes including pseudoenzymes2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 234, p. 80-84Article in journal (Refereed)
    Abstract [en]

    Mammalian alcohol dehydrogenase (ADH) is a protein family divided into six classes and the number of known family members is increasing rapidly. Several primate genomes are completely analyzed for the ADH region, where higher primates (human and hominoids) have seven genes of classes ADH1-ADH5. Within the group of non-hominoids apes there have been further duplications and species with more than the typical three isozymic forms for ADH1 are present. In contrast there are few completely analyzed ADH genomes in the non-primate group of mammals, where an additional class has been identified, ADH6, that has been lost during the evolution of primates. In this study 85 mammalian genomes with at least one ADH gene have been compiled. In total more than 500 ADH amino acid sequences were analyzed for patterns that distinguish the different classes. For ADH1-ADH4 intensive investigations have been performed both at the functional and at structural levels. However, a corresponding functional protein to the ADH5 gene, which is found in most ADH genomes, has never been detected. The same is true for ADH6, which is only present in non-primates. The entire mammalian ADH family shows a broad spectrum of gene duplications and gene losses where the numbers differ from six genes (most non-primate mammals) up to ten genes (vole). Included in these sets are examples of pseudogenes and pseudoenzymes.

  • 9. Ryge, Marija Rakonjac
    et al.
    Tanabe, Michiharu
    Provost, Patrick
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Chen, Xinsheng
    Funk, Colin D.
    Rinaldo-Matthis, Agnes
    Hofmann, Bettina
    Steinhilber, Dieter
    Watanabe, Takashi
    Samuelsson, Bengt
    Radmark, Olof
    A mutation interfering with 5-lipoxygenase domain interaction leads to increased enzyme activity2014In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 545, p. 179-185Article in journal (Refereed)
    Abstract [en]

    5-Lipoxygenase (5-LOX) catalyzes two steps in conversion of arachidonic acid to proinflammatory leukotrienes. Lipoxygenases, including human 5-LOX, consist of an N-terminal C2-like beta-sandwich and a catalytic domain. We expressed the 5-LOX domains separately, these were found to interact in the yeast two-hybrid system. The 5-LOX structure suggested association between Arg(101) in the beta-sandwich and Asp(166) in the catalytic domain, due to electrostatic interaction as well as hydrogen bonds. Indeed, mutagenic replacements of these residues led to loss of two-hybrid interaction. Interestingly, when Arg(101) was mutated to Asp in intact 5-LOX, enzyme activity was increased. Thus, higher initial velocity of the reaction (v(init)) and increased final amount of products were monitored for 5-LOX-R101D, at several different assay conditions. In the 5-LOX crystal structure, helix alpha 2 and adjacent loops (including Asp(166)) of the 5-LOX catalytic domain has been proposed to form a flexible lid controlling access to the active site, and lid movement would be determined by bonding of lid residues to the C2-like beta-sandwich. The more efficient catalysis following disruption of the R101-D166 ionic association supports the concept of such a flexible lid in human 5-LOX. (C) 2014 Elsevier Inc. All rights reserved.

  • 10.
    Stodberg, Tommy
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Neuropediat Unit, SE-17176 Stockholm, Sweden..
    McTague, Amy
    UCL Inst Child Hlth, Dev Neurosci Programme, Mol Neurosci, London WC1N 1EH, England.;Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England..
    Ruiz, Arnaud J.
    UCL Sch Pharm, Dept Pharmacol, London WC1N 1AX, England..
    Hirata, Hiromi
    Aoyama Gakuin Univ, Grad Sch Sci & Engn, Dept Chem & Biol Sci, Sagamihara, Kanagawa 2525258, Japan.;Natl Inst Genet, Ctr Frontier Res, Mishima, Shizuoka 4118540, Japan.;Japan Sci & Technol Agcy, PREST, Tokyo 1020076, Japan..
    Zhen, Juan
    NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA..
    Long, Philip
    UCL Sch Pharm, Dept Pharmacol, London WC1N 1AX, England..
    Farabella, Irene
    Univ London, Birkbeck Coll, Crystallog Dept Biol Sci, Inst Struct & Mol Biol, London WC1E 7HX, England..
    Meyer, Esther
    UCL Inst Child Hlth, Dev Neurosci Programme, Mol Neurosci, London WC1N 1EH, England..
    Kawahara, Atsuo
    Univ Yamanashi, Grad Sch Med Sci, Dev Biol Lab, Chuo Ku, Kofu, Yamanashi 4093898, Japan..
    Vassallo, Grace
    Royal Manchester Childrens Hosp, Dept Neurol, Manchester M13 9WL, Lancs, England..
    Stivaros, Stavros M.
    Royal Manchester Childrens Hosp, Acad Dept Radiol, Manchester M13 9WL, Lancs, England.;Univ Manchester, Sch Populat Hlth, Imaging Sci, Manchester M13 9PL, Lancs, England..
    Bjursell, Magnus K.
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Sci Life Lab, SE-17176 Stockholm, Sweden..
    Stranneheim, Henrik
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Inherited Metab Dis, SE-17176 Stockholm, Sweden..
    Tigerschiold, Stephanie
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Sci Life Lab, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Inherited Metab Dis, SE-17176 Stockholm, Sweden..
    Persson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bangash, Iftikhar
    Royal Oldham Hosp, EEG Dept, Oldham OL1 2JH, Lancs, England..
    Das, Krishna
    Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England.;Young Epilepsy, Lingfield RH7 6PW, Surrey, England..
    Hughes, Deborah
    UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England..
    Lesko, Nicole
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Lundeberg, Joakim
    Royal Inst Technol, Sci Life Lab, Sch Biotechnol, SE-10044 Stockholm, Sweden..
    Scott, Rod C.
    Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England.;Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT 05405 USA.;Fletcher Allen Hlth Care, Dept Paediat Neurol, Vermont, VT 05401 USA.;UCL Inst Child Hlth, Dev Neurosci Programme, Clin Neurosci, London WC1N 1EH, England..
    Poduri, Annapurna
    Boston Childrens Hosp, Epilepsy Genet Programme, Dept Neurol, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA..
    Scheffer, Ingrid E.
    Univ Melbourne, Austin Hlth, Dept Med & Paediat, Melbourne, Vic 3052, Australia.;Royal Childrens Hosp, Melbourne, Vic 3052, Australia.;Florey Inst, Melbourne, Vic 3010, Australia..
    Smith, Holly
    UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England..
    Gissen, Paul
    UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England.;Great Ormond St Hosp Sick Children, Dept Metab Med, London WC1N 3JH, England.;UCL, Inst Child Hlth, Genet & Genom Med, London WC1N 1EH, England..
    Schorge, Stephanie
    UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England..
    Reith, Maarten E. A.
    NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA..
    Topf, Maya
    Univ London, Birkbeck Coll, Crystallog Dept Biol Sci, Inst Struct & Mol Biol, London WC1E 7HX, England..
    Kullmann, Dimitri M.
    UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England..
    Harvey, Robert J.
    UCL Sch Pharm, Dept Pharmacol, London WC1N 1AX, England..
    Wedell, Anna
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Sci Life Lab, SE-17176 Stockholm, Sweden..
    Kurian, Manju A.
    UCL Inst Child Hlth, Dev Neurosci Programme, Mol Neurosci, London WC1N 1EH, England.;Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England..
    Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8038Article in journal (Refereed)
    Abstract [en]

    The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.

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