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Persson, Bengt
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Karlsson, L., Michelatto, D. d., Gori Lusa, A. L., Mgnani Silva, C. D., Ostberg, L. J., Persson, B., . . . Lajic, S. (2019). Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia. Clinical Biochemistry, 73, 50-56
Öppna denna publikation i ny flik eller fönster >>Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia
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2019 (Engelska)Ingår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 73, s. 50-56Artikel i tidskrift (Refereegranskat) Published
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.

 

Nyckelord
21-hydroxylase, Functional studies, Congenital adrenal hyperplasia, Synergistic effects
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-397413 (URN)10.1016/j.clinbiochem.2019.07.009 (DOI)000492745500007 ()31344365 (PubMedID)
Forskningsfinansiär
JerringfondenStockholms läns landstingMarianne och Marcus Wallenbergs Stiftelse
Tillgänglig från: 2019-11-20 Skapad: 2019-11-20 Senast uppdaterad: 2019-11-20Bibliografiskt granskad
Ison, J., Ienasescu, H., Chmura, P., Rydza, E., Menager, H., Kalas, M., . . . Brunak, S. (2019). The bio.tools registry of software tools and data resources for the life sciences. Genome Biology, 20(1), Article ID 164.
Öppna denna publikation i ny flik eller fönster >>The bio.tools registry of software tools and data resources for the life sciences
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2019 (Engelska)Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, nr 1, artikel-id 164Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BMC, 2019
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-393613 (URN)10.1186/s13059-019-1772-6 (DOI)000480534400002 ()31405382 (PubMedID)
Forskningsfinansiär
EU, Horisont 2020, 676559
Tillgänglig från: 2019-09-27 Skapad: 2019-09-27 Senast uppdaterad: 2019-09-27Bibliografiskt granskad
Das, S., Frisk, C., Eriksson, M. J., Walentinsson, A., Corbascio, M., Hage, C., . . . Persson, B. (2019). Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction. Scientific Reports, 9, Article ID 3179.
Öppna denna publikation i ny flik eller fönster >>Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction
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2019 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 3179Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2019
Nationell ämneskategori
Kardiologi
Identifikatorer
urn:nbn:se:uu:diva-379578 (URN)10.1038/s41598-019-39445-2 (DOI)000459897600113 ()30816197 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseVetenskapsrådet
Tillgänglig från: 2019-04-12 Skapad: 2019-04-12 Senast uppdaterad: 2019-04-12Bibliografiskt granskad
Asp, M., Salmen, F., Ståhl, P. L., Vickovic, S., Felldin, U., Löfling, M., . . . Lundeberg, J. (2017). Spatial detection of fetal marker genes expressed at low level in adult human heart tissue. Scientific Reports, 7, Article ID 12941.
Öppna denna publikation i ny flik eller fönster >>Spatial detection of fetal marker genes expressed at low level in adult human heart tissue
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2017 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 12941Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2017
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:uu:diva-338515 (URN)10.1038/s41598-017-13462-5 (DOI)000412781300009 ()29021611 (PubMedID)
Forskningsfinansiär
AstraZenecaKnut och Alice Wallenbergs StiftelseStiftelsen för strategisk forskning (SSF)VetenskapsrådetScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Tillgänglig från: 2018-01-15 Skapad: 2018-01-15 Senast uppdaterad: 2018-01-15Bibliografiskt granskad
Barbaro, M., Soardi, F. C., Ostberg, L. J., Persson, B., de Mello, M. P., Wedell, A. & Lajic, S. (2015). In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia. Clinical Endocrinology, 82(1), 37-44
Öppna denna publikation i ny flik eller fönster >>In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia
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2015 (Engelska)Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, nr 1, s. 37-44Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-242377 (URN)10.1111/cen.12526 (DOI)000346788000007 ()
Tillgänglig från: 2015-01-26 Skapad: 2015-01-26 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Stodberg, T., McTague, A., Ruiz, A. J., Hirata, H., Zhen, J., Long, P., . . . Kurian, M. A. (2015). Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nature Communications, 6, Article ID 8038.
Öppna denna publikation i ny flik eller fönster >>Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
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2015 (Engelska)Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 8038Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Pediatrik Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-267073 (URN)10.1038/ncomms9038 (DOI)000362945300001 ()26333769 (PubMedID)
Forskningsfinansiär
EU, Europeiska forskningsrådetVetenskapsrådet, 12198Wellcome trustStockholms läns landstingKnut och Alice Wallenbergs StiftelseNIH (National Institute of Health)
Tillgänglig från: 2015-11-20 Skapad: 2015-11-17 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Ostberg, L. J., Persson, B. & Hoog, J.-O. (2015). The mammalian alcohol dehydrogenase genome shows several gene duplications and gene losses resulting in a large set of different enzymes including pseudoenzymes. Chemico-Biological Interactions, 234, 80-84
Öppna denna publikation i ny flik eller fönster >>The mammalian alcohol dehydrogenase genome shows several gene duplications and gene losses resulting in a large set of different enzymes including pseudoenzymes
2015 (Engelska)Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 234, s. 80-84Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Alcohol dehydrogenase, Gene duplications, Phylogenetic tree, Protein sequences, Pseudoenzyme
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-256804 (URN)10.1016/j.cbi.2014.11.020 (DOI)000355044000010 ()25479062 (PubMedID)
Tillgänglig från: 2015-06-29 Skapad: 2015-06-26 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Ryge, M. R., Tanabe, M., Provost, P., Persson, B., Chen, X., Funk, C. D., . . . Radmark, O. (2014). A mutation interfering with 5-lipoxygenase domain interaction leads to increased enzyme activity. Archives of Biochemistry and Biophysics, 545, 179-185
Öppna denna publikation i ny flik eller fönster >>A mutation interfering with 5-lipoxygenase domain interaction leads to increased enzyme activity
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2014 (Engelska)Ingår i: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 545, s. 179-185Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Leukotriene, Eicosanoid, Arachidonic acid, Two-hybrid system, Domain interaction
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-222931 (URN)10.1016/j.abb.2014.01.017 (DOI)000332751700022 ()
Tillgänglig från: 2014-04-17 Skapad: 2014-04-15 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Baltscheffsky, H. & Persson, B. (2014). On an Early Gene for Membrane-Integral Inorganic Pyrophosphatase in the Genome of an Apparently Pre-LUCA Extremophile, the Archaeon Candidatus Korarchaeum cryptofilum. Journal of Molecular Evolution, 78(2), 140-147
Öppna denna publikation i ny flik eller fönster >>On an Early Gene for Membrane-Integral Inorganic Pyrophosphatase in the Genome of an Apparently Pre-LUCA Extremophile, the Archaeon Candidatus Korarchaeum cryptofilum
2014 (Engelska)Ingår i: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 78, nr 2, s. 140-147Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Archaeon, Extremophile, Pyrophosphatase, miPPase, Energy, Evolution, Bioinformatics
Nationell ämneskategori
Cellbiologi Evolutionsbiologi
Identifikatorer
urn:nbn:se:uu:diva-227576 (URN)10.1007/s00239-014-9610-7 (DOI)000335888100005 ()
Tillgänglig från: 2014-06-30 Skapad: 2014-06-27 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Norling, A., Hirschberg, A. L., Iwarsson, E., Persson, B., Wedell, A. & Barbaro, M. (2013). Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform. European Journal of Medical Genetics, 56(12), 661-668
Öppna denna publikation i ny flik eller fönster >>Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform
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2013 (Engelska)Ingår i: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, nr 12, s. 661-668Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Array-CGH, C2ORF80, Disorders of sex development, Gonadal dysgenesis, SUPT3H, PIP5K1B
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-213906 (URN)10.1016/j.ejmg.2013.09.003 (DOI)000327718500004 ()
Tillgänglig från: 2014-01-06 Skapad: 2014-01-05 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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