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Structural Impact (structural + impact)

Distribution by Scientific Domains

Life Sciences	40%

Selected Abstracts

Differential functional effects of novel mutations of the transcription factor FOXL2 in BPES patients,

HUMAN MUTATION, Issue 8 2008
Jeyabalan Nallathambi
Abstract Mutations of the transcription factor FOXL2, involved in cranio-facial and ovarian development lead to the Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) in human. Here, we describe nine mutations in the open reading frame of FOXL2. Six of them are novel: c.292T>A (p.Trp98Arg), c.323T>C (p.Leu108Pro), c.650C>G (p.Ser217Cys) and three frameshifts. We have performed localization and functional studies for three of them. We have observed a strong cytoplasmic mislocalization induced by the missense mutation p.Leu108Pro located in the forkhead (FKH) domain of FOXL2. In line with this, transcriptional activity assays confirmed the loss-of-function induced by this variant. Interestingly, the novel mutation p.Ser217Cys, mapping between the FKH and the polyalanine domain of FOXL2 and producing a mild eyelid phenotype, led to normal localization and transactivation. We have also modeled the structure of the FKH domain to explore the potential structural impact of the mutations reported here and other previously reported ones. This analysis shows that mutants can be sorted into two classes: those that potentially alter protein-protein interactions and those that might disrupt the interactions with DNA. Our findings reveal new insights into the molecular effects of FOXL2 mutations, especially those affecting the FKH binding domain. © 2008 Wiley-Liss, Inc. [source]

Neuroimaging of cortical development and brain connectivity in human newborns and animal models

JOURNAL OF ANATOMY, Issue 4 2010
Gregory A. Lodygensky
Abstract Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype. [source]

Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure

BRITISH JOURNAL OF DERMATOLOGY, Issue 5 2010
B. Je, ábková
Summary Background, Epidermolysis bullosa simplex (EBS) is an inherited skin disorder caused by mutations in the keratin 5 (KRT5) and keratin 14 (KRT14) genes, with fragility of basal keratinocytes leading to epidermal cytolysis and blistering. Objectives, In this study, we characterized mutations in KRT5 and KRT14 genes in patients with EBS and investigated their possible structure,function correlations. Materials and methods, Mutations were characterized using polymerase chain reaction (PCR) and DNA sequencing. Further, to explore possible correlations with function, the structural effects of the mutations in segment 2B of KRT5 and KRT14 and associated with EBS in our patients, as well as those reported previously, were modelled by molecular dynamics with the aid of the known crystal structure of the analogous segment of human vimentin. Results, We have identified mutations in the KRT5 and KRT14 genes in 16 of 23 families affected by EBS in the Czech Republic. Eleven different sequence variants were found, of which four have not been reported previously. Novel mutations were found in two patients with the EBS-Dowling,Meara variant (EBS-DM) [KRT14-p.Ser128Pro and KRT14-p.Gln374_Leu387dup(14)] and in three patients with localized EBS (KRT14-p.Leu136Pro and KRT5-p.Val143Ala). Molecular dynamics studies show that the mutations p.Glu411del and p.Ile467Thr perturb the secondary alpha-helical structure of the mutated polypeptide chain, the deletion p.Glu411del in KRT14 has a strong but only local influence on the secondary structure of KRT14, and the structural impact of the mutation p.Ile467Thr in KRT5 is spread along the helix to the C-terminus. In all the other point mutations studied, the direct structural impact was significantly weaker and did not destroy the alpha-helical pattern of the secondary protein structure. The changes of 3-D structure of the KRT5/KRT14 dimer induced by the steric structural impact of the single point mutations, and the resulting altered inter- and intramolecular contacts, are spread along the protein helices to the protein C-terminus, but the overall alpha-helical character of the secondary structure is not destroyed and the atomic displacements induced by mutations cause only limited-scale changes of the quaternary structure of the dimer. Conclusions, The results of molecular modelling show relationships between patients' phenotypes and the structural effects of individual mutations. [source]

Ligand Reprogramming in Dinuclear Helicate Complexes: A Consequence of Allosteric or Electrostatic Effects?

CHEMISTRY - A EUROPEAN JOURNAL, Issue 18 2007

Abstract The ditopic ligand 6,6,-bis(4-methylthiazol-2-yl)-3,3,-([18]crown-6)-2,2,-bipyridine (L1) contains both a potentially tetradentate pyridyl-thiazole (py-tz) N - donor chain and an additional "external" crown ether binding site which spans the central 2,2,-bipyridine unit. In polar solvents (MeCN, MeNO2) this ligand forms complexes with ZnII, CdII, HgII and CuI ions via coordination of the N donors to the metal ion. Reaction with both HgII and CuI ions results in the self-assembly of dinuclear double-stranded helicate complexes. The ligands are partitioned by rotation about the central pypy bond, such that each can coordinate to both metals as a bis-bidentate donor ligand. With ZnII ions a single-stranded mononuclear species is formed in which one ligand coordinates the metal ion in a planar tetradentate fashion. Reaction with CdII ions gives rise to an equilibrium between both the dinuclear double-stranded helicate and the mononuclear species. These complexes can further coordinate s-block metal cations via the remote crown ether O - donor domains; a consequence of which are some remarkable changes in the binding modes of the N-donor domains. Reaction of the HgII - or CdII -containing helicate with either Ba2+ or Sr2+ ions effectively reprogrammes the ligand to form only the single-stranded heterobinuclear complexes [MM,(L1)]4+ (M=HgII, CdII; M,=Ba2+, Sr2+), where the transition and s-block cations reside in the N- and O-donor sites, respectively. In contrast, the same ions have only a minor structural impact on the ZnII species, which already exists as a single-stranded mononuclear complex. Similar reactions with the CdII system result in a shift in equilibrium towards the single-stranded species, the extent of which depends on the size and charge of the s-block cation in question. Reaction of the dicopper(I) double-stranded helicate with Ba2+ shows that the dinuclear structure still remains intact but the pitch length is significantly increased. [source]