Mauno Vihinen
Lund University, Experimental Medical Science, Faculty Member
- Professor Medical Structural Biology since 2012edit
Research Interests: Genetics, Human, Humans, Mutation, Male, and 14 moreInfant, Genetic linkage analysis, Clinical Sciences, Insertion, Btk, X chromosome, Base Sequence, X-linked Agammaglobulinemia, Agammaglobulinemia, DNA mutational analysis, Child preschool, Human mutation, Bruton Tyrosine Kinase, and Protein tyrosine kinases
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Research Interests: Biological Sciences, Cell line, Humans, Mutation, Haplotypes, and 16 moreFemale, Animals, Male, Human Molecular Genetics, Polymerase Chain Reaction, Infant, Newborn Infant, Introns, Spectrum, Amino Acid Sequence, Base Sequence, Autosomal Recessive, Osteopetrosis, Vacuoles, Molecular Sequence Data, and DNA mutational analysis
Variations in mismatch repair (MMR) system genes are causative of Lynch syndrome and other cancers. Thousands of variants have been identified in MMR genes, but the clinical relevance is known for only a small proportion. Recently, the... more
Variations in mismatch repair (MMR) system genes are causative of Lynch syndrome and other cancers. Thousands of variants have been identified in MMR genes, but the clinical relevance is known for only a small proportion. Recently, the InSiGHT group classified 2,360 MMR variants into five classes. One-third of variants, majority of which is nonsynonymous variants, remain to be of uncertain clinical relevance. Computational tools can be used to prioritize variants for disease relevance investigations. Previously, we classified 248 MMR variants as likely pathogenic and likely benign using PON-MMR. We have developed a novel tool, PON-MMR2, which is trained on a larger and more reliable dataset. In performance comparison, PON-MMR2 outperforms both generic tolerance prediction methods as well as methods optimized for MMR variants. It achieves accuracy and MCC of 0.89 and 0.78, respectively, in cross-validation and 0.86 and 0.69, respectively, on an independent test dataset. We classified 354 class 3 variants in InSiGHT database as well as all possible amino acid substitutions in four MMR proteins. Likely harmful variants mainly appear in the protein core, whereas likely benign variants are on the surface. PON-MMR2 is a highly reliable tool to prioritize variants for functional analysis. It is freely available at http://structure.bmc.lu.se/PON-MMR2/.
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Variations in proteins have very large number of diverse effects affecting sequence, structure, stability, interactions, activity, abundance and other properties. Although protein-coding exons cover just over 1 % of the human genome they... more
Variations in proteins have very large number of diverse effects affecting sequence, structure, stability, interactions, activity, abundance and other properties. Although protein-coding exons cover just over 1 % of the human genome they harbor an disproportionately large portion of disease-causing variants. Variation ontology (VariO) has been developed for annotation and description of variation effects, mechanisms and consequences. A holistic view for variations in proteins is made available along with examples of real cases. Protein variants can be of genetic origin or emerge at protein level. Systematic names are provided for all variation types, a more detailed description can be made by explaining changes to protein function, structure and properties. Examples are provided for the effects and mechanisms, usually in relation to human diseases. In addition, the examples are selected so that protein 3D structural changes, when relevant, are included and visualized. Here, systemat...
Research Interests: Genetics, Human Genetics, Molecular Dynamics Simulation, Protein Folding, Complementary and Alternative Medicine, and 9 moreHumans, Animals, Gene ontology, Proteins, Protein Secondary Structure Prediction, Genetic variation, Amino Acid Sequence, Protein Quaternary Structure, and Structure activity Relationship
Several immunodeficiency-related genes have been identified and a large number of mutations in these genes. Currently, a genetic defect has been determined in more than 2000 patients. Only recently has it become possible to address... more
Several immunodeficiency-related genes have been identified and a large number of mutations in these genes. Currently, a genetic defect has been determined in more than 2000 patients. Only recently has it become possible to address structure-function effects of these mutations in the corresponding proteins. The consequences of mutations in structure are discussed for Btk in X-linked agammaglobulinemia (XLA), Jak3 in T-B+ severe combined immunodeficiency (SCID), p47phox and p67phox in autosomal chronic granulomatous disease (CGD) and SH2D1 A in X-linked lymphoproliferatine disease (XLP). The experimental and homology modelling derived structures were used to analyze mechanisms related to these diseases.
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B-cell development into antibody producing cells is a complex process that relies on the tightly controlled production of hundreds of genes and proteins. A B-cell is activated through the B-cell receptor (BCR) and this activation is... more
B-cell development into antibody producing cells is a complex process that relies on the tightly controlled production of hundreds of genes and proteins. A B-cell is activated through the B-cell receptor (BCR) and this activation is modified by different co-stimulatory or inhibitory co-receptors. The concerted action of signals from BCR and from co-receptors decides the fate of the B-cells. The majority of B-cells enter apoptosis, while some of them progress through the cell cycle and become, for example, antibody producing plasma cells. We studied BCR stimulated Ramos B-cells to explore the expression of BCR pathway, cell cycle and apoptosis related genes. We followed, using microarrays, the gene expression for several days after BCR engagement. Several bioinformatics methods were used to investigate the properties and common features of co-expressed genes. Certain gene ontologies have statistically significant enrichment into clusters of similarly expressed genes. The cell signaling pathways and gene expression data were combined to reveal detailed information about biological processes and B-cell systems biology. The results provide knowledge of the development of adaptive immunity and clues about how the pathways are affected by regulation of the expression of genes.
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Computational prediction methods are widely used for the analysis of human genome sequence variants and their effects on gene/protein function, splice site aberration, pathogenicity, and disease risk. New methods are frequently developed.... more
Computational prediction methods are widely used for the analysis of human genome sequence variants and their effects on gene/protein function, splice site aberration, pathogenicity, and disease risk. New methods are frequently developed. We believe that guidelines are essential for those writing articles about new prediction methods, as well as for those applying these tools in their research, so that the necessary details are reported. This will enable readers to gain the full picture of technical information, performance, and interpretation of results, and to facilitate comparisons of related methods. Here, we provide instructions on how to describe new methods, report datasets, and assess the performance of predictive tools. We also discuss what details of predictor implementation are essential for authors to understand. Similarly, these guidelines for the use of predictors provide instructions on what needs to be delineated in the text, as well as how researchers can avoid unwarranted conclusions. They are applicable to most prediction methods currently utilized. By applying these guidelines, authors will help reviewers, editors, and readers to more fully comprehend prediction methods and their use.
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Signal transduction pathways are crucial for the regulation of a very wide variety of cellular functions ranging, for example, from translation to intercellular communication, and from metabolism to apoptosis. Protein kinases and... more
Signal transduction pathways are crucial for the regulation of a very wide variety of cellular functions ranging, for example, from translation to intercellular communication, and from metabolism to apoptosis. Protein kinases and phosphatases, together with their binding partners, are key players in these cascades. They also form a substantial part of the genes in genomes and proteins in proteomes in all animals. Signalling can be studied in many different levels and ways. This has resulted in large body of publications and Internet services. This paper describes open-access databases and software aiming at presenting the kind of data available and how to perform bioinformatics analyses.
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... [16] Kadziola, A., Abe, Ji, Svensson, B. and ... 200 U. Lamminmiiki, M. Vihinen Biochimica et Biophysica Acta 1295 (1996) 195200 [21] Bernstein, FC, Koetzle, TF, Williams, GJB, Meyer, EF,Brice, MD, Rodgers, JR, Kennard, O.,... more
... [16] Kadziola, A., Abe, Ji, Svensson, B. and ... 200 U. Lamminmiiki, M. Vihinen Biochimica et Biophysica Acta 1295 (1996) 195200 [21] Bernstein, FC, Koetzle, TF, Williams, GJB, Meyer, EF,Brice, MD, Rodgers, JR, Kennard, O., Shimanouchi, T. and Tasumi, M. (1977) J. Mol. Biol. ...
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It is generally considered mammals and birds have five Tec family kinases (TFKs): Btk, Bmx (also known as Etk), Itk, Tec, and Txk (also known as Rlk). Here, we discuss the domains and their functions and regulation in TFKs. Over the last... more
It is generally considered mammals and birds have five Tec family kinases (TFKs): Btk, Bmx (also known as Etk), Itk, Tec, and Txk (also known as Rlk). Here, we discuss the domains and their functions and regulation in TFKs. Over the last few years, a large number of genomes from various phyla have been sequenced making it possible to study
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Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains among the human protein kinases the highest number of unique disease-causing... more
Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains among the human protein kinases the highest number of unique disease-causing variations, still it is just 10% of all the possible single nucleotide substitution-caused amino acid variations. In the BTK kinase domain (BTK-KD) can appear altogether 1495 such variants. We investigated them all with bioinformatic and protein structure analysis methods. Most disease-causing variations affect conserved and buried residues disturbing protein stability. Minority of exposed residues is conserved, but strongly tied to pathogenicity. 67% of the variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, while in 10% of sites all the substitutions are tolerated. Results indicate the importance of the entire kinase domain, involvement in numerous interactions, and intricate functional regulation ...
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Translocation-associated gene fusions are well recognized in acute myeloid leukemia. Other molecular genetic changes are less well known. The novel cDNA technology has opened the avenue to large-scale gene expression analysis. Our aim was... more
Translocation-associated gene fusions are well recognized in acute myeloid leukemia. Other molecular genetic changes are less well known. The novel cDNA technology has opened the avenue to large-scale gene expression analysis. Our aim was to perform cDNA microarray analysis of acute myeloid leukemia (AML). We performed cDNA microarray analysis using the Clontech hematology filter (containing 406 genes) on 15 patients to study gene expression profiling in AML. As reference, we used whole bone marrow from 5 healthy donors. Our results revealed 50 differentially expressed genes in at least 3 out of 15 patients. Twenty-two genes were upregulated (ratio > or =4), whereas 28 genes were downregulated (ratio < or =0.25). All but one of the 13 genes tested by real-time polymerase chain reaction (PCR) showed the same expression profiles. Among the overexpressed genes, several were those earlier associated with chromosomal translocations and gene fusions. These genes were FGFR1, MYC, NPM...
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The Btk (Bruton's tyrosine kinase) gene has been shown to be mutated in the human immunodeficiency disease, XLA (X-linked agammaglobulinemia). Btk is a member of the Tec family of cytosolic protein tyrosine kinases with distinct... more
The Btk (Bruton's tyrosine kinase) gene has been shown to be mutated in the human immunodeficiency disease, XLA (X-linked agammaglobulinemia). Btk is a member of the Tec family of cytosolic protein tyrosine kinases with distinct functional domains PH, TH, SH3, SH2, and kinase. Mutations have been observed in each of the Btk subdomains in XLA. We have analyzed the Btk gene in six XLA patients from five unrelated families. DNA was prepared from the patients peripheral blood. The Btk exons including the junctional sequences were analyzed by single-strand conformation polymorphism (SSCP) followed by direct nucleotide sequencing after PCR-amplification. For structural analysis, the missense mutations were introduced into three-dimensional models of the PH and kinase domains of Btk and the outcome was predicted based on the knowledge of the protein function. Five novel mutations and two novel polymorphisms, all of which resulted from single-base alterations, were identified. Three of ...
Aspartylglucosaminidase (AGA, EC 3.5.1.26) is an essential enzyme in the degradation of asparagine-linked glycoproteins. In man, deficient activity of this enzyme leads to aspartylglucosaminuria (AGU), a recessively inherited lysosomal... more
Aspartylglucosaminidase (AGA, EC 3.5.1.26) is an essential enzyme in the degradation of asparagine-linked glycoproteins. In man, deficient activity of this enzyme leads to aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease. Here we used affinity-purified polyclonal antibodies against the native AGA and its denatured subunits to establish the molecular structure and intracellular location of the enzyme in normal and AGU fibroblasts. Inactivation of the enzyme was found to coincide with the dissociation of the heterodimeric enzyme complex into subunits. Although the subunits were not linked by covalent forces, the intrapolypeptide disulphide bridges were found to be essential for the normal function of AGA. AGA was localized into lysosomes in control fibroblasts by both immunofluorescence microscopy and immuno-electron microscopy, whereas in AGU cells the location of antigen was different, suggesting that, owing to the mutation, a missing disulphide bridge...
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Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated... more
Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated ...
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Essential human immunome is composed of about 900 genes and proteins. Primary immunodeficiencies (IDs) are a large and heterogenic group of inherited disorders of the immune system. Since defects in any part of the adaptive or innate... more
Essential human immunome is composed of about 900 genes and proteins. Primary immunodeficiencies (IDs) are a large and heterogenic group of inherited disorders of the immune system. Since defects in any part of the adaptive or innate immune system can cause disorders, numerous IDs have been detected. Immunodeficiency patients have increased susceptibility to recurrent and persistent, even life-threatening infections. Other
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B-cell development to antibody-producing plasma cells requires the concerted function of a large number of genes and proteins. Genome-level expression profiling during human B-cell maturation was studied in anti-immunoglobulin... more
B-cell development to antibody-producing plasma cells requires the concerted function of a large number of genes and proteins. Genome-level expression profiling during human B-cell maturation was studied in anti-immunoglobulin M-stimulated Ramos cells. cDNA microarrays were used to follow changes in the transcriptome over several days. Close to 1500 genes had significantly altered expression at least at one time point. The genes were organized into clusters based on expression profiles and were further characterized based on the functions of the coded proteins. Several groups of genes important for B cells were analyzed. Here we concentrate on genes involved in signal transduction and cytokines and their receptors. The results provide knowledge on the development of humoral immunity. Several new genes were found to be essential for B-cell development. They can be used as targets for research and possibly for drug development.
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The previously identified QTL for oleic acid content observed in an F2 population from the Brassica rapa ssp. oleifera cross Jo4002 × Jo4072 (a high-oleic-acid individual) was mapped more precisely by adding markers to the linkage group... more
The previously identified QTL for oleic acid content observed in an F2 population from the Brassica rapa ssp. oleifera cross Jo4002 × Jo4072 (a high-oleic-acid individual) was mapped more precisely by adding markers to the linkage group which harbours the locus. In addition, the fad2 gene, which is known to encode the 18:1 desaturase in Arabidopsis, was mapped in Brassica, too. The results are consistent with the QTL corresponding to the Arabidopsis fad2 gene. Comparison of the wild-type and high-oleic-acid allele of the locus revealed only one difference in their nucleic acid sequences leading to an amino acid change. This substitution of leucine by proline most likely affects the fold of the protein and thereby activity of the enzyme. Using this base difference, an allele-specific PCR was designed. The allele-specific markers will be very effective in selection for plants with high-oleic-acid content derived from Jo4072 because they are located exactly at the locus and can differentiate between homo- and heterozygotes.
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The current research considers the approximate string matching search for important subsequences from DNA sequences, which is essential for numerous bioinformatics computation tasks. We tested several approximate string matching... more
The current research considers the approximate string matching search for important subsequences from DNA sequences, which is essential for numerous bioinformatics computation tasks. We tested several approximate string matching algorithms and furthermore developed one for DNA data. Run times of the algorithms are important, since the amount of data is very large.
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Research Interests: Algorithms, Computational Biology, Biological Sciences, Software, Phylogeny, and 10 moreSequence alignment, Computer Simulation, Mathematical Sciences, BMC Bioinformatics, Protein structure, Quality assessment, Importance Sampling, Phylogenetic Tree, Multiple Sequence Alignment, and Amino Acid Sequence
Computational tools are essential for most of our research. To use these tools, one needs to know how they work. Problems in application of computational methods to variation analysis can appear at several stages and affect, for example,... more
Computational tools are essential for most of our research. To use these tools, one needs to know how they work. Problems in application of computational methods to variation analysis can appear at several stages and affect, for example, the interpretation of results. Such cases are discussed along with suggestions how to avoid them. The applications include incomplete reporting of methods, especially about the use of prediction tools; method selection on unscientific grounds and without consulting independent method performance assessments; extending application area of methods outside their intended purpose; use of the same data several times for obtaining majority vote; and filtering of datasets so that variants of interest are excluded. All these issues can be avoided by discontinuing the use software tools as black boxes.
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The assessment of residue conservation in a multiple sequence alignment is a central issue in bioinformatics. Conserved residues and regions are used to determine structural and functional motifs or evolutionary relationships between the... more
The assessment of residue conservation in a multiple sequence alignment is a central issue in bioinformatics. Conserved residues and regions are used to determine structural and functional motifs or evolutionary relationships between the sequences of a multiple sequence alignment. For this reason, residue conservation is a valuable measure for database and motif search or for estimating the quality of alignments. In this paper, we present statistical methods for identifying conserved residues in multiple sequence alignments. While most earlier studies examine the positional conservation of the alignment, we focus on the detection of individual conserved residues at a position. The major advantages of multiple comparison methods originate from their ability to select conserved residues simultaneously and to consider the variability of the residue estimates. Large-scale simulations were used for the comparative analysis of the methods. Practical performance was studied by comparing the structurally and functionally important residues of Src homology 2 (SH2) domains to the assignments of the conservation indices. The applicability of the indices was also compared in three additional protein families comprising different degrees of entropy and variability in alignment positions. The results indicate that statistical multiple comparison methods are sensitive and reliable in identifying conserved residues.
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We report the structure of a novel tetrameric form of the lactose repressor (LacI) protein from Escherichia coli refined to 2.1 A resolution. The tetramer is bound to 1.6-hexanediol present in the crystallization solution and the final... more
We report the structure of a novel tetrameric form of the lactose repressor (LacI) protein from Escherichia coli refined to 2.1 A resolution. The tetramer is bound to 1.6-hexanediol present in the crystallization solution and the final R(free) for the structure is 0.201. The structure confirms previously reported structures on the monomer level. However, the tetramer is much more densely packed. This adds a new level of complexity to the interpretation of mutational effects and challenges details in the current model for LacI function. Several amino acids, previously associated with changes in function but unexplained at the structural level, appear in a new structural context in this tetramer which provides new implications for their function.
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Thermostability of proteins arises from the simultaneous effect of several forces, which in fact lead to decreased flexibility of the polypeptide chain. This is verified by flexibility indices, which are derived from normalized B-values... more
Thermostability of proteins arises from the simultaneous effect of several forces, which in fact lead to decreased flexibility of the polypeptide chain. This is verified by flexibility indices, which are derived from normalized B-values of individual amino acids in several refined three-dimensional structures. Flexibility indices show that overall flexibility is reduced when thermostability is increased. Protein molecules require both flexibility and rigidity to function, but the higher the temperature optimum and stability the more rigid is the structure needed to compensate for increased thermal fluctuations. Flexibilities of proteins performing the same catalytic activity seem to be about the same at their temperature optima, but the more rigid thermostable proteins reach the flexibility of thermolabile proteins at higher temperatures. In several proteins such as allosteric enzymes, some local sites of flexibility are highly conserved. The relevance of reduced flexibility to overall stability of proteins is also discussed. Flexibility indices and profiles can be used in the design of more stable proteins by site-directed mutagenesis.