Search results for "MUTATION"
showing 10 items of 2830 documents
Genotype–phenotype correlation in a new Fabry-disease-causing mutation
2019
Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical a…
PRENATAL IDENTIFICATION OF A HETEROZYGOUS STATUS IN TWO FETUSES AT RISK FOR GLUCOSE–GALACTOSE MALABSORPTION
1996
Glucose-galactose malabsorption (GGM) is an autosomal recessive disorder which presents with severe osmotic diarrhoea shortly after birth. Two proband siblings with GGM were previously demonstrated to contain a missense mutation (D28N) in the Na + -dependent glucose/galactose cotransporter (SGLTI) that accounts for the defect in sugar absorption. Prenatal screening for GGM was performed in two subsequent pregnancies in this large consanguineous family. The first exon of the SGLTI gene was PCR-amplified from genomic DNA and screened for the presence of the D28N mutation by EcoRV restriction digestion. The proband's sibling was heterozygous and a cousin was not a carrier of the D28N mutation.…
Decentralization and heterogeneity in complex adaptative systems
2015
Purpose – Following a bacterial-based modeling approach, the authors want to model and analyze the impact of both decentralization and heterogeneity on group behavior and collective learning. The paper aims to discuss these issues. Design/methodology/approach – Inspired by bacterial conjugation, the authors have defined an artificial society in which agents’ strategies adapt to changes in resources location, allowing migration, and survival in a dynamic sugarscape-like scenario. To study the impact of these variables the authors have simulated a scenario in which resources are limited and localized. The authors also have defined three constraints in genetic information processing (inhibiti…
HSP70, the Key to Account for Erythroid Tropism of Diamond-Blackfan Anemia?
2015
Abstract Diamond-Blackfan anemia (DBA) was the first ribosomopathy identified and is characterized by a moderate to severe, usually macrocytic aregenerative anemia associated with congenital malformations in 50% of the DBA cases. This congenital rare erythroblastopenia is due to a blockade in erythroid differentiation between the BFU-e and CFU-e stages. The link between a haploinsufficiency in a ribosomal protein (RP) gene that now encompass 15 different RP genes and the erythroid defect is still to be fully defined. Recently, mutations in TSR2 and GATA1 genes have been identified in a few DBA families. The GATA1 gene encodes for the major transcription factor critical for erythropoiesis an…
Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O6-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by …
2008
Abstract O 6 -methylguanine (O 6 MeG) is a highly critical DNA adduct induced by methylating carcinogens and anticancer drugs such as temozolomide, streptozotocine, procarbazine and dacarbazine. Induction of cell death by O 6 MeG lesions requires mismatch repair (MMR) and cell proliferation and is thought to be dependent on the formation of DNA double-strand breaks (DSBs) or, according to an alternative hypothesis, direct signaling by the MMR complex. Given a role for DSBs in this process, either homologous recombination (HR) or non-homologous end joining (NHEJ) or both might protect against O 6 MeG. Here, we compared the response of cells mutated in HR and NHEJ proteins to temozolomide and…
Cisplatin-induced apoptosis in 43-3B and 27-1 cells defective in nucleotide excision repair
2001
Cisplatin is a highly potent cytotoxic and genotoxic agent used in the chemotherapy of various types of tumors. Its cytotoxic effect is supposed to be due to the induction of intra- and interstrand DNA cross-links which are repaired via the nucleotide excision repair (NER) pathway. Here, we elucidated the mechanism of cisplatin-induced cytotoxicity in mutants derived from CHO-9 cells defective in NER. We compared 43-3B and 27-1 cells deficient for ERCC1 and ERCC3, respectively, with the corresponding wild-type and ERCC1 complemented 43-3B cells. It is shown that cells defective in ERCC1 are more sensitive than cells defective in ERCC3 with regard to cisplatin-induced reproductive cell death…
Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin
2000
An association between oncogenic transformation and repression of different components of the MHC class I antigen processing machinery (APM) have been described in murine model systems. In order to discover whether a similar correlation exists, human tumor cell lines of distinct histology with altered ras protein were analyzed for the expression of APM components utilizing RT-PCR and Western blot analyses. A heterogeneous expression pattern of MHC class I antigens, TAP peptide transporter, proteasome subunits, proteasome activator PA28 and the chaperones calnexin, calreticulin as well as tapasin was displayed by these tumor cell lines. Single or combined deficiencies in the expression and/o…
Thermal Isomerization Mechanism in Dronpa and Its Mutants.
2016
The photoswitching speed of the reversibly switchable fluorescent proteins (RSFPs) from the family of green fluorescent proteins (GFPs) changes upon mutation which is of direct importance for various high-resolution techniques. Dronpa is one of the most used RSFPs. Its point mutants rsFastLime (Dronpa V157G) and rsKame (Dronpa V157L) exhibit a striking difference in their photoswitching speed. Here the QM/MM on-the-fly string method is used in order to explore the details of the thermal isomerization mechanism. The four principal ways in which isomerization may occur have been scrutinized for each of the three proteins. It has been shown that thermal isomerization occurs via a one-bond-flip…
High affinity agonistic metal ion binding sites within the melanocortin 4 receptor illustrate conformational change of transmembrane region 3.
2003
We created a molecular model of the human melanocortin 4 receptor (MC4R) and introduced a series of His residues into the receptor protein to form metal ion binding sites. We were able to insert micromolar affinity binding sites for zinc between transmembrane region (TM) 2 and TM3 where the metal ion alone was able to activate this peptide binding G-protein-coupled receptor. The exact conformation of the metal ion interactions allowed us to predict the orientation of the helices, and remodeling of the receptor protein indicated that Glu100 and Ile104 in TM2 and Asp122 and Ile125 in TM3 are directed toward a putative area of activation of the receptor. The molecular model suggests that a rot…
Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.
2009
Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Recent structural studies have shown that neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the actual mechanism of receptor activation has remained elusive. Here we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p7…