Crystallins and hereditary cataracts: molecular mechanisms and potential for therapy

2006 ◽  
Vol 8 (25) ◽  
pp. 1-19 ◽  
Author(s):  
Usha P. Andley
Keyword(s):  
Molecular Mechanisms ◽  
Single Point ◽  
Point Mutations ◽  
Major Protein ◽  
Ageing Population ◽  
Age Related ◽  
Genes Encoding ◽  
Mechanisms Of Formation ◽  
Variable Morphology ◽  
Protein Components

Hereditary childhood cataracts can arise from single-point mutations in genes encoding crystallins, the major protein components of the lens. The cataracts are most commonly inherited by an autosomal dominant mechanism. The nature of the changes in the lens resulting from these point mutations in crystallin genes has not been fully characterised. While aggregation and light scattering associated with expression of the mutant crystallin protein may be an end point, it is also necessary to determine the progression of changes induced at the level of development and differentiation. A key finding in recent work is that cell death or cytotoxicity is associated with mutations in αA-crystallin. The variable morphology or localisation of the cataract in different pedigrees, even with the identical crystallin gene mutation, has led to the idea that other environmental or genetic factors interact to give the final lens phenotype. The study of mechanisms of formation of hereditary cataracts may lead to a greater understanding of the mechanisms that lead to age-related cataracts, a very common cause of blindness in the ageing population.

scholarly journals The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies

2018 ◽  
Vol 19 (12) ◽  
pp. 3975 ◽  
Author(s):  
Yurii Borovikov ◽  
Olga Karpicheva ◽  
Armen Simonyan ◽  
Stanislava Avrova ◽  
Elena Rogozovets ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Point Mutations ◽  
Nemaline Myopathy ◽  
Muscle Dysfunction ◽  
Thin Filaments ◽  
Mutant Proteins ◽  
Strong Binding ◽  
Genes Encoding

Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca2+, which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca2+ which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca2+ was observed for all mutations associated with high Ca2+-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.

scholarly journals A configurable model of the synaptic proteome reveals the molecular mechanisms of disease co-morbidity

2020 ◽  
Author(s):  
Oksana Sorokina ◽  
Colin Mclean ◽  
Mike DR Croning ◽  
Katharina F Heil ◽  
Emilia Wysocka ◽  
...  
Keyword(s):  
Network Model ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Network Models ◽  
Disease Association ◽  
Synaptic Proteins ◽  
Protein Interaction Data ◽  
Co Morbidity ◽  
Genes Encoding ◽  
Protein Components

AbstractSynapses contain highly complex proteomes which control synaptic transmission, cognition and behaviour. Genes encoding synaptic proteins are associated with neuronal disorders many of which show clinical co-morbidity. Our hypothesis is that there is mechanistic overlap that is emergent from the network properties of the molecular complex. To test this requires a detailed and comprehensive molecular network model.We integrated 57 published synaptic proteomic datasets obtained between 2000 and 2019 that describe over 7000 proteins. The complexity of the postsynaptic proteome is reaching an asymptote with a core set of ~3000 proteins, with less data on the presynaptic terminal, where each new study reveals new components in its landscape. To complete the network, we added direct protein-protein interaction data and functional metadata including disease association.The resulting amalgamated molecular interaction network model is embedded into a SQLite database. The database is highly flexible allowing the widest range of queries to derive custom network models based on meta-data including species, disease association, synaptic compartment, brain region, and method of extraction.This network model enables us to perform in-depth analyses that dissect molecular pathways of multiple diseases revealing shared and unique protein components. We can clearly identify common and unique molecular profiles for co-morbid neurological disorders such as Schizophrenia and Bipolar Disorder and even disease comorbidities which span biological systems such as the intersection of Alzheimer’s Disease with Hypertension.

scholarly journals Identification of Point Mutations in Clinical Staphylococcus aureus Strains That Produce Small-Colony Variants Auxotrophic for Menadione

2014 ◽  
Vol 82 (4) ◽  
pp. 1600-1605 ◽  
Author(s):  
Melissa A. Dean ◽  
Randall J. Olsen ◽  
S. Wesley Long ◽  
Adriana E. Rosato ◽  
James M. Musser
Keyword(s):  
Staphylococcus Aureus ◽  
Pathway Analysis ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Biosynthesis Pathway ◽  
Wild Type ◽  
Small Colony Variants ◽  
Content Type ◽  
Genes Encoding ◽  
Small Colony

ABSTRACTStaphylococcus aureussmall-colony variants (SCVs) are implicated in chronic and relapsing infections that are difficult to diagnose and treat. Despite many years of study, the underlying molecular mechanisms and virulence effect of the small-colony phenotype remain incompletely understood. We sequenced the genomes of fiveS. aureusSCV strains recovered from human patients and discovered previously unidentified nonsynonymous point mutations in three genes encoding proteins in the menadione biosynthesis pathway. Analysis of genetic revertants and complementation with wild-type alleles confirmed that these mutations caused the SCV phenotype and decreased virulence for mice.

Molecular Pathogenesis of MDS

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 156-160 ◽  
Author(s):  
A. Thomas Look
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Suppressor Genes ◽  
Hematopoietic Stem ◽  
Chromosomal Deletions ◽  
Genes Encoding

Abstract Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q–, 5q–, 20q–, 6q–, 11q– and 13q–) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench1 and Fenaux2). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD.3 Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells,4 the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (α-catenin) and c/EBPα, and implicating these genes as tumor suppressors.5–7 Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q– and (del)5q.

scholarly journals Mutations in Aspergillus fumigatus Resulting in Reduced Susceptibility to Posaconazole Appear To Be Restricted to a Single Amino Acid in the Cytochrome P450 14α-Demethylase

2003 ◽  
Vol 47 (2) ◽  
pp. 577-581 ◽  
Author(s):  
Paul A. Mann ◽  
Raulo M. Parmegiani ◽  
Shui-Qing Wei ◽  
Cara A. Mendrick ◽  
Xin Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Aspergillus Fumigatus ◽  
Single Point ◽  
Point Mutations ◽  
Drug Accumulation ◽  
Resistant Isolate ◽  
Single Amino Acid ◽  
Single Point Mutation ◽  
Genes Encoding ◽  
Moderately Resistant

ABSTRACT To better understand the molecular basis of posaconazole (POS) resistance in Aspergillus fumigatus, resistant laboratory isolates were selected. Spontaneous mutants arose at a frequency of 1 in 108 and fell into two susceptibility groups, moderately resistant and highly resistant. Azole resistance in A. fumigatus was previously associated with decreased drug accumulation. We therefore analyzed the mutants for changes in levels of transcripts of genes encoding efflux pumps (mdr1 and mdr2) and/or alterations in accumulation of [14C]POS. No changes in either pump expression or drug accumulation were detected. Similarly, there was no change in expression of cyp51A or cyp51B, which encode the presumed target site for POS, cytochrome P450 14α-demethylase. DNA sequencing revealed that each resistant isolate carried a single point mutation in residue 54 of cyp51A. Mutations at the same locus were identified in three clinical A. fumigatus isolates exhibiting reduced POS susceptibility but not in susceptible clinical strains. To verify that these mutations were responsible for the resistance phenotype, we introduced them into the chromosome of a POS-susceptible A. fumigatus strain under the control of the glyceraldehyde phosphate dehydrogenase promoter. The transformants exhibited reductions in susceptibility to POS comparable to those exhibited by the original mutants, confirming that point mutations in the cyp51A gene in A. fumigatus can confer reduced susceptibility to POS.

scholarly journals Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

2017 ◽  
Vol 114 (42) ◽  
pp. 11115-11120 ◽  
Author(s):  
Binnu Gangadharan ◽  
Margaret S. Sunitha ◽  
Souhrid Mukherjee ◽  
Ritu Roy Chowdhury ◽  
Farah Haque ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Troponin T ◽  
Point Mutations ◽  
Structural Features ◽  
Sarcomeric Proteins ◽  
Binding Assays ◽  
Genes Encoding ◽  
The Stability ◽  
Insight Into

Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the TNNT2 gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80–180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT. HCM mutants were hypersensitive and DCM mutants were hyposensitive to Ca2+ in regulated actomyosin ATPase activities. To gain better insight into the disease mechanism, we modeled the structure of TNT1 and its interactions with Tm. The stability predictions made by the model correlated well with the affinity changes observed in vitro of TnT mutants for Tm. The changes in Ca2+ sensitivity showed a strong correlation with the changes in binding affinity. We suggest the primary reason by which these TNNT2 mutations between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the TNT1 region.

scholarly journals Molecular Mechanisms of Succinimide Formation from Aspartic Acid Residues Catalyzed by Two Water Molecules in the Aqueous Phase

2021 ◽  
Vol 22 (2) ◽  
pp. 509
Author(s):  
Tomoki Nakayoshi ◽  
Koichi Kato ◽  
Shuichi Fukuyoshi ◽  
Ohgi Takahashi ◽  
Eiji Kurimoto ◽  
...  
Keyword(s):  
Gas Phase ◽  
Aspartic Acid ◽  
Aqueous Phase ◽  
Molecular Mechanisms ◽  
Model Compound ◽  
Reaction Pathway ◽  
Single Point ◽  
Water Molecules ◽  
Age Related ◽  
Optimized Geometries

Aspartic acid (Asp) residues are prone to nonenzymatic isomerization via a succinimide (Suc) intermediate. The formation of isomerized Asp residues is considered to be associated with various age-related diseases, such as cataracts and Alzheimer’s disease. In the present paper, we describe the reaction pathway of Suc residue formation from Asp residues catalyzed by two water molecules using the B3LYP/6-31+G(d,p) level of theory. Single-point energies were calculated using the MP2/6-311+G(d,p) level of theory. For these calculations, we used a model compound in which an Asp residue was capped with acetyl and methylamino groups on the N- and C-termini, respectively. In the aqueous phase, Suc residue formation from an Asp residue was roughly divided into three steps, namely, iminolization, cyclization, and dehydration, with the activation energy estimated to be 109 kJ mol−1. Some optimized geometries and reaction modes in the aqueous phase were observed that differed from those in the gas phase.

scholarly journals Gene duplications and gene loss in the epidermal differentiation complex during the evolutionary land-to-water transition of cetaceans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Karin Brigit Holthaus ◽  
Julia Lachner ◽  
Bettina Ebner ◽  
Erwin Tschachler ◽  
Leopold Eckhart
Keyword(s):  
Genetic Regulation ◽  
Skin Barrier ◽  
Specific Protein ◽  
Epidermal Differentiation ◽  
Major Protein ◽  
Cornified Envelope ◽  
Terrestrial Mammals ◽  
Epidermal Differentiation Complex ◽  
Genes Encoding ◽  
Protein Components

AbstractMajor protein components of the mammalian skin barrier are encoded by genes clustered in the Epidermal Differentiation Complex (EDC). The skin of cetaceans, i.e. whales, porpoises and dolphins, differs histologically from that of terrestrial mammals. However, the genetic regulation of their epidermal barrier is only incompletely known. Here, we investigated the EDC of cetaceans by comparative genomics. We found that important epidermal cornification proteins, such as loricrin and involucrin are conserved and subtypes of small proline-rich proteins (SPRRs) are even expanded in numbers in cetaceans. By contrast, keratinocyte proline rich protein (KPRP), skin-specific protein 32 (XP32) and late-cornified envelope (LCE) genes with the notable exception of LCE7A have been lost in cetaceans. Genes encoding proline rich 9 (PRR9) and late cornified envelope like proline rich 1 (LELP1) have degenerated in subgroups of cetaceans. These data suggest that the evolution of an aquatic lifestyle was accompanied by amplification of SPRR genes and loss of specific other epidermal differentiation genes in the phylogenetic lineage leading to cetaceans.

Preliminary evidence of differential expression of myogenic and stress factors in skeletal muscle of older adults with low muscle strength

2022 ◽  
Author(s):  
Sebastiaan Dalle ◽  
Jolan Dupont ◽  
Lenore Dedeyne ◽  
Sabine Verschueren ◽  
Jos Tournoy ◽  
...  
Keyword(s):  
Older Adults ◽  
Muscle Strength ◽  
Molecular Mechanisms ◽  
Citrate Synthase ◽  
Inflammatory Marker ◽  
Stress Factors ◽  
Test Time ◽  
Ageing Population ◽  
Strength Group ◽  
Age Related

Abstract The age-related loss of muscle strength and mass, or sarcopenia, is a growing concern in the ageing population. Yet, it is not fully understood which molecular mechanisms underlie sarcopenia. Therefore, the present study compared the protein expression profile, such as catabolic, oxidative, stress-related and myogenic pathways, between older adults with preserved (8 ♀ and 5 ♂; 71.5 ±2.6 years) and low muscle strength (6 ♀ and 5 ♂; 78.0±5.0 years). Low muscle strength was defined as chair stand test time >15 seconds and/or handgrip strength <16kg (women) or <27kg (men) according the EWGSOP2 criteria. Catabolic signaling (i.e. FOXO1/3a, MuRF1, MAFbx, LC3b, Atg5, p62) was not differentially expressed between both groups, whereas the mitochondrial marker COX-IV, but not PGC1α and citrate synthase, was lower in the low muscle strength group. Stress factors CHOP and p-ERK1/2 were higher (~1.5-fold) in older adults with low muscle strength. Surprisingly, the inflammatory marker p-p65NF-κB was ~7-fold higher in older adults with preserved muscle strength. Finally, expression of myogenic factors (i.e. Pax7, MyoD, desmin; ~2-fold) was higher in adults with low muscle strength. To conclude, whereas the increased stress factors might reflect the age-related deterioration of tissue homeostasis, e.g. due to misfolded proteins (CHOP), upregulation of myogenic markers in the low strength group might be an attempt to compensate for the gradual loss in muscle quantity and quality. These data might provide valuable insights in the processes that underlie sarcopenia.

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