Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms

2008 ◽  
pp. 73-87
Author(s):  
Evangelia Charmandari ◽  
Tomoshige Kino ◽  
George P. Chrousos
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

2021 ◽  
Author(s):  
Wen-Qiang Zheng ◽  
Signe Vandal Pedersen ◽  
Kyle Thompson ◽  
Emanuele Bellacchio ◽  
Courtney E French ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Homology Modelling ◽  
Mitochondrial Diseases ◽  
Trna Synthetase ◽  
Unrelated Patient ◽  
Mitochondrial Translation ◽  
Respiratory Chain Enzyme ◽  
Functional Studies ◽  
Pathogenic Variants

Abstract TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Additionally, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modelling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

scholarly journals DNA methylation patterns associated with cyanogenic cassava exposure and konzo in Sub-Saharan Africa

2021 ◽  
Author(s):  
Kristen Kocher ◽  
Surajit Bhattacharya ◽  
Matthew Scott Bramble ◽  
Daniel Okitundu-Luwa ◽  
Dieudonne Mumba Ngoyi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Spastic Paraparesis ◽  
Dietary Exposure ◽  
Sub Saharan Africa ◽  
Healthy Controls ◽  
Biological Processes ◽  
Bitter Cassava ◽  
Sub Saharan ◽  
Methylation Patterns

Konzo, a disease characterized by sudden, irreversible spastic paraparesis, affecting up to 10% of the population in some regions of Sub-Saharan Africa during outbreaks and is strongly associated with dietary exposure to cyanogenic bitter cassava. The molecular mechanisms underlying the development of konzo, remain largely unknown. Here, through an analysis of 16 individuals with konzo and matched healthy controls from the same outbreak zones, we identified 117 differentially methylated loci involved in numerous biological processes that may identify cyanogenic- sensitive regions of the genome, providing the first study of epigenomic alterations associated with sub-lethal cyanide exposure and a clinical phenotype.

Familial/Sporadic Glucocorticoid Resistance: Clinical Phenotype and Molecular Mechanisms

2004 ◽  
Vol 1024 (1) ◽  
pp. 168-181 ◽  
Author(s):  
EVANGELIA CHARMANDARI ◽  
TOMOSHIGE KINO ◽  
GEORGE P. CHROUSOS
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Glucocorticoid Resistance

scholarly journals Alagille Syndrome: Diagnostic Challenges and Advances in Management

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 907
Author(s):  
Mohammed D. Ayoub ◽  
Binita M. Kamath
Keyword(s):  
Bile Duct ◽  
Molecular Basis ◽  
Clinical Characteristics ◽  
Molecular Mechanisms ◽  
Clinical Phenotype ◽  
Alagille Syndrome ◽  
Comprehensive Overview ◽  
Multisystem Disease ◽  
Therapeutic Concepts ◽  
Near Future

Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart, eyes, skeleton, face, kidneys, and vasculature. The identification of JAG1 and NOTCH2 as disease-causing genes has deepened our understanding of the molecular mechanisms underlying ALGS. However, the variable expressivity of the clinical phenotype and the lack of genotype-phenotype relationships creates significant diagnostic and therapeutic challenges. In this review, we provide a comprehensive overview of the clinical characteristics and management of ALGS, and the molecular basis of ALGS pathobiology. We further describe unique diagnostic considerations that pose challenges to clinicians and outline therapeutic concepts and treatment targets that may be available in the near future.

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

1992 ◽  
Vol 50 (1) ◽  
pp. 450-451
Author(s):  
David P. Bazett-Jones ◽  
Mark L. Brown
Keyword(s):  
Transcription Factor ◽  
Dna Sequences ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Phosphorus Content ◽  
Spectroscopic Imaging ◽  
Electron Spectroscopic Imaging ◽  
Dna Backbone ◽  
Two Parameters ◽  
High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

Dissection of the molecular mechanisms of protein targeting to the peroxisome using immunofluorescence and immunocryoelectron microscopies

1990 ◽  
Vol 48 (3) ◽  
pp. 44-45
Author(s):  
G-A. Keller ◽  
S. J. Gould ◽  
S. Subramani ◽  
S. Krisans
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Protein Targeting ◽  
Firefly Luciferase ◽  
Peroxisomal Enzyme ◽  
Transfected Cells ◽  
Peroxisomal Targeting ◽  
Targeting Signal ◽  
Series Of Experiments ◽  
Peroxisomal Targeting Signal

Subcellular compartments within eukaryotic cells must each be supplied with unique sets of proteins that must be directed to, and translocated across one or more membranes of the target organelles. This transport is mediated by cis- acting targeting signals present within the imported proteins. The following is a chronological account of a series of experiments designed and carried out in an effort to understand how proteins are targeted to the peroxisomal compartment.-We demonstrated by immunocryoelectron microscopy that the enzyme luciferase is a peroxisomal enzyme in the firefly lantern. -We expressed the cDNA encoding firefly luciferase in mammalian cells and demonstrated by immunofluorescence that the enzyme was transported into the peroxisomes of the transfected cells. -Using deletions, linker insertions, and gene fusion to identify regions of luciferase involved in its transport to the peroxisomes, we demonstrated that luciferase contains a peroxisomal targeting signal (PTS) within its COOH-terminal twelve amino acid.

High resolution mapping of nucleic acid containing complexes in vitro and in situ

1996 ◽  
Vol 54 ◽  
pp. 48-49
Author(s):  
D. P. Bazett-Jones ◽  
M. J. Hendzel
Keyword(s):  
Nucleic Acid ◽  
High Resolution ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Heavy Atom ◽  
Regulation Of Transcription ◽  
High Exposure ◽  
Resolution Mapping ◽  
Tata Sequence

Structural analysis of combinations of nucleosomes and transcription factors on promoter and enhancer elements is necessary in order to understand the molecular mechanisms responsible for the regulation of transcription initiation. Such complexes are often not amenable to study by high resolution crystallographic techniques. We have been applying electron spectroscopic imaging (ESI) to specific problems in molecular biology related to transcription regulation. There are several advantages that this technique offers in studies of nucleoprotein complexes. First, an intermediate level of spatial resolution can be achieved because heavy atom contrast agents are not necessary. Second, mass and stoichiometric relationships of protein and nucleic acid can be estimated by phosphorus detection, an element in much higher proportions in nucleic acid than protein. Third, wrapping or bending of the DNA by the protein constituents can be observed by phosphorus mapping of the complexes. Even when ESI is used with high exposure of electrons to the specimen, important macromolecular information may be provided. For example, an image of the TATA binding protein (TBP) bound to DNA is shown in the Figure (top panel). It can be seen that the protein distorts the DNA away from itself and much of its mass sits off the DNA helix axis. Moreover, phosphorus and mass estimates demonstrate whether one or two TBP molecules interact with this particular promoter TATA sequence.

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