| 1. |
- Aspatwar, Ashok, et al.
(författare)
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Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:3, s. 417-432
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Tidskriftsartikel (refereegranskat)abstract
- Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.
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| 2. |
- Ortutay, Csaba, et al.
(författare)
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Conserved and Quickly Evolving Immunome Genes Have Different Evolutionary Paths
- 2012
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 33:10, s. 1456-1463
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Tidskriftsartikel (refereegranskat)abstract
- Genetic, transcript, and protein level variations have important functional and evolutionary consequences. We performed systematic data collection and analysis of copy-number variations, single-nucleotide polymorphisms, disease-causing variations, messenger RNA splicing variants, and protein posttranslational modifications for the genes and proteins essential for human immune system. Information about polymorphic and evolutionarily fixed genetic variations was used to group immunome genes to the most conserved and the most quickly changing ones under directed selection during the recent immunome evolution. Gene Ontology terms related to adaptive immunity are associated with gene groups subject to recent directing selection. In addition, several other characteristics of the immunome genes and proteins in these two categories have statistically significant differences. The presented findings question the usability of directed mouse genes as models for human diseases and conditions and shed light on the fine tuning of human immunity and its diverse functions. HumMutat 33:1456-1463, 2012. (C) 2012 Wiley Periodicals, Inc.
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| 3. |
- Teku, Gabriel, et al.
(författare)
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Identification of core T cell network based on immunome interactome.
- 2014
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Ingår i: BMC Systems Biology. - : Springer Science and Business Media LLC. - 1752-0509. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI) networks facilitate investigation and identification of proteins important for particular processes or diseases and reduces time and costs of experimental verification. Modeling the dynamics of very large PPI networks is computationally costly.
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| 4. |
- Valiaho, Jouni, et al.
(författare)
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Characterization of All Possible Single-Nucleotide Change Caused Amino Acid Substitutions in the Kinase Domain of Bruton Tyrosine Kinase
- 2015
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 36:6, s. 638-647
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about features distinguishing deleterious and neutral variations is crucial for interpretation of novel variants. Bruton tyrosine kinase (BTK) contains the highest number of unique disease-causing variations among the human protein kinases, still it is just 10% of all the possible single-nucleotide substitution-caused amino acid variations (SNAVs). In the BTK kinase domain (BTK-KD) can appear altogether 1,495 SNAVs. 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. Sixty-seven percent of variations are predicted to be harmful. In 39% of the residues, all the variants are likely harmful, whereas 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 by conformational change. These results can be extended to other protein kinases and organisms.
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