ADOLESCENT CYSTINOSIS: COMPARISONS WITH INFANTILE AND ADULT FORMS

PEDIATRICS ◽  
1971 ◽  
Vol 47 (6) ◽  
pp. 979-988
Author(s):  
H. Goldman ◽  
C. R. Scriver ◽  
K. Aaron ◽  
E. Delvin ◽  
Z. Canlas
Keyword(s):  
Steady State ◽  
Gene Dosage ◽  
Intracellular Concentration ◽  
Gene Products ◽  
Clinical Prognosis ◽  
Cystine Content ◽  
Infantile Cystinosis ◽  
New Form

Two adolescent siblings with a new form of cystinosis are distinctive because of their present age (15 and 14 years), their mild nephropathy, and the absence of retinopathy and pigmentary changes. The intracellular concentration of free cystine in their fibroblasts and leukocytes is 3 to 6 µmoles/gm protein, which is lower than in fatal infantile cystinosis and slightly higher than in the benign adult trait. The cystine is localized predominantly in the "granular" fraction. Both parents of the adolescent cystinotic siblings have excessive cystine retention in fibroblasts and leukocytes in the range which is typical of infantile cystinotic heterozygotes but cystine storage is not directly proportional to gene dosage. Dithiothreitol reduces the cystine content of "adolescent" fibroblasts, as it does in "infantile" cells. The three cystinotic traits indicate that several mutant alleles, at one or more gene loci, affect one or more gene products which control the steady-state of cystine metabolism in the cell. Clinical prognosis is apparently influenced to some extent by the severity of cystine retention.

scholarly journals Aneuploidy and gene expression: is there dosage compensation?

Epigenomics ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1827-1837 ◽  
Author(s):  
Shihoko Kojima ◽  
Daniela Cimini
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Current Knowledge ◽  
Gene Dosage ◽  
Congenital Defects ◽  
Gene Products ◽  
Epigenetic Changes ◽  
Transcript Levels ◽  
Compensation Mechanisms ◽  
Additional Chromosome

Aneuploidy (i.e., abnormal chromosome number) is the leading cause of miscarriage and congenital defects in humans. Moreover, aneuploidy is ubiquitous in cancer. The deleterious phenotypes associated with aneuploidy are likely a result of the imbalance in the levels of gene products derived from the additional chromosome(s). Here, we summarize the current knowledge on how the presence of extra chromosomes impacts gene expression. We describe studies that have found a strict correlation between gene dosage and transcript levels as wells as studies that have found a less stringent correlation, hinting at the possible existence of dosage compensation mechanisms. We conclude by peering into the epigenetic changes found in aneuploid cells and outlining current knowledge gaps and potential areas of future investigation.

scholarly journals A stochastic model of gene expression with polymerase recruitment and pause release

2019 ◽  
Author(s):  
Z. Cao ◽  
T. Filatova ◽  
D. A. Oyarzún ◽  
R. Grima
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Rna Polymerase ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Relative Sensitivity ◽  
Recruitment Rate ◽  
Time Dependent ◽  
Steady State Distribution ◽  
State Distribution

AbstractTranscriptional bursting is a major source of noise in gene expression. The telegraph model of gene expression, whereby transcription switches between “on” and “off” states, is the dominant model for bursting. Recently it was shown that the telegraph model cannot explain a number of experimental observations from perturbation data. Here we study an alternative model that is consistent with the data and which explicitly describes RNA polymerase recruitment and polymerase pause release, two steps necessary for mRNA production. We derive the exact steady-state distribution of mRNA numbers and an approximate steady-state distribution of protein numbers which are given by generalized hypergeometric functions. The theory is used to calculate the relative sensitivity of the coefficient of variation of mRNA fluctuations for thousands of genes in mouse fibroblasts. This indicates that the size of fluctuations is mostly sensitive to the rate of burst initiation and the mRNA degradation rate. Furthermore we show that (i) the time-dependent distribution of mRNA numbers is accurately approximated by a modified telegraph model with a Michaelis-Menten like dependence of the effective transcription rate on RNA polymerase abundance. (ii) the model predicts that if the polymerase recruitment rate is comparable or less than the pause release rate, then upon gene replication the mean number of RNA per cell remains approximately constant. This gene dosage compensation property has been experimentally observed and cannot be explained by the telegraph model with constant rates.Statement of SignificanceThe random nature of gene expression is well established experimentally. Mathematical modelling provides a means of understanding the factors leading to the observed stochasticity. There is evidence that the classical two-state model of stochastic mRNA dynamics (the telegraph model) cannot describe perturbation experiments and a new model that includes polymerase dynamics has been proposed. In this paper, we present the first detailed study of this model, deriving an exact solution for the mRNA distribution in steady-state conditions, an approximate time-dependent solution and showing the model can explain gene dosage compensation. As well, we use the theory together with transcriptomic data, to deduce which parameters when perturbed lead to a maximal change in the size of mRNA fluctuations.

scholarly journals A note on “Taylor–Couette flow of a generalized second grade fluid due to a constant couple”

2010 ◽  
Vol 15 (2) ◽  
pp. 155-158 ◽  
Author(s):  
C. Fetecau ◽  
A. U. Awan ◽  
M. Athar
Keyword(s):  
Exact Solution ◽  
Steady State ◽  
Unsteady Flow ◽  
Couette Flow ◽  
Second Grade ◽  
Second Grade Fluid ◽  
Grade Fluid ◽  
Generalized Second Grade Fluid ◽  
New Form ◽  
Second Grade Fluids

In this brief note, we show that the unsteady flow of a generalized second grade fluid due to a constant couple, as well as the similar flow of Newtonian and ordinary second grade fluids, ultimately becomes steady. For this, a new form of the exact solution for velocity is established. This solution is presented as a sum of the steady and transient components. The required time to reach the steady-state is obtained by graphical illustrations.

scholarly journals Role of STE genes in the mating factor signaling pathway mediated by GPA1 in Saccharomyces cerevisiae.

1988 ◽  
Vol 8 (9) ◽  
pp. 3777-3783 ◽  
Author(s):  
N Nakayama ◽  
Y Kaziro ◽  
K Arai ◽  
K Matsumoto
Keyword(s):  
Steady State ◽  
Signaling Pathway ◽  
State Level ◽  
G1 Arrest ◽  
Gene Products ◽  
Mating Efficiency ◽  
Protein Functions ◽  
Steady State Levels ◽  
Mating Factor

The ste mutants (ste2, ste4, ste5, ste7, ste11, and ste12) are insensitive to mating factors and are, therefore, sterile. Roles of the STE gene products in the GPA1-mediated mating factor signaling pathway were studied by using ste gpa1 double mutants. Mating efficiency of a ste2 mutant defective in the alpha-factor receptor increased 1,000-fold in a gpa1 background, while G1 arrest and aberrant morphology (shmoo) caused by gpa1 were not suppressed by ste2. Furthermore, the steady-state level of the FUS1 transcript, which normally increases in response to mating factors, was also elevated when the GPA1 function was impaired. These results suggest that the GPA1 protein functions downstream of the STE2 receptor. Conversely, the sterility of ste4, ste5, ste7, ste11, and ste12 mutants was not suppressed by gpa1, but the lethal phenotype of gpa1 was suppressed by these ste mutations. Northern (RNA) blotting analysis revealed that the ste7, ste11, and ste12 mutations caused reductions of 50 to 70% in the steady-state levels of the GPA1 transcript, while ste4 had a slight effect and ste5 had no effect. This implies that the suppression by ste7, ste11, and ste12 could be due to reduced syntheses of additional components, including an effector, and that suppression by ste4 and ste5 may result from direct effects on the signaling pathway. The STE4, STE5, STE7, STE11, and STE12 products, therefore, appear to specify components of the signal transduction machinery, directly or indirectly, which function together with or downstream of GPA1.

scholarly journals tuf Gene Dosage Effects on the Intracellular Concentration of EF-TuB

1983 ◽  
Vol 130 (2) ◽  
pp. 409-417 ◽  
Author(s):  
Peter H. MEIDE ◽  
Rob A. KASTELEIN ◽  
Erik VIJGENBOOM ◽  
Leendert BOSCH
Keyword(s):  
Gene Dosage ◽  
Intracellular Concentration ◽  
Tuf Gene ◽  
Gene Dosage Effects ◽  
Dosage Effects

Transport of PAH, urate, TEA, and fluid by isolated perfused and nonperfused avian renal proximal tubules

1994 ◽  
Vol 266 (4) ◽  
pp. R1085-R1094 ◽  
Author(s):  
O. H. Brokl ◽  
E. J. Braun ◽  
W. H. Dantzler
Keyword(s):  
Steady State ◽  
Basolateral Membrane ◽  
Proximal Tubules ◽  
Intracellular Concentration ◽  
Electrochemical Gradient ◽  
Bathing Medium ◽  
Renal Proximal Tubules ◽  
Electrical Gradient ◽  
High Concentrations ◽  
First Time

Transport of organic anions [p-aminohippurate (PAH) and urate] and organic cations [tetraethylammonium (TEA)] and reabsorption of fluid were studied for the first time in individual renal proximal tubules isolated from avian kidneys. In isolated nonperfused tubules, PAH and urate uptake occurred against electrochemical gradients, whereas TEA uptake appeared to result from the electrical gradient. Radiolabeled PAH uptake and radiolabeled urate uptake were inhibited to an equal extent by high concentrations of unlabeled PAH and probenecid, suggesting that they might share the same transport system. However, the rate of uptake of radiolabeled PAH was significantly stimulated by preloading with alpha-ketoglutarate (alpha-KG), suggesting PAH/alpha-KG countertransport as in mammals and reptiles, whereas uptake of radiolabeled urate was not clearly stimulated. In isolated perfused tubules, net fluid reabsorption averaged approximately 2 nl.min-1.mm-1 and was inhibited by ouabain with or without bicarbonate in the perfusate and bathing medium. In these perfused tubules, the unidirectional bath-to-lumen fluxes of PAH and urate exceeded the unidirectional lumen-to-bath fluxes, indicating net secretion of both compounds. During the bath-to-lumen fluxes the uptake across the basolateral membrane was against an electrochemical gradient for both compounds. However, for PAH the steady-state intracellular concentration was about half that observed in nonperfused tubules, as generally expected during net secretion, whereas for urate the steady-state intracellular concentration was about twice that observed in nonperfused tubules, suggesting stimulation of uptake during net secretion. During the PAH lumen-to-bath flux, the steady-state intracellular concentration was significantly above that in the perfusate, suggesting that this flux involved transport into the cells from the lumen against an electrochemical gradient. However, during the urate lumen-to-bath flux, there was no urate in the cells, suggesting that this flux, as in reptiles, occurred by a paracellular route.

scholarly journals Limited expression of non-integrating CpG-free plasmid is associated with increased nucleosome enrichment

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244386
Author(s):  
Omar Habib ◽  
Rozita Mohd Sakri ◽  
Nadiah Ghazalli ◽  
De-Ming Chau ◽  
King-Hwa Ling ◽  
...  
Keyword(s):  
Steady State ◽  
Transgene Expression ◽  
Gene Dosage ◽  
Expression Profiles ◽  
Mrna Level ◽  
Gene Transfer Agent ◽  
Expression Potential ◽  
Steady State Mrna Level

CpG-free pDNA was reported to facilitate sustained transgene expression with minimal inflammation in vivo as compared to CpG-containing pDNA. However, the expression potential and impact of CpG-free pDNA in in vitro model have never been described. Hence, in this study, we analyzed the transgene expression profiles of CpG-free pDNA in vitro to determine the influence of CpG depletion from the transgene. We found that in contrast to the published in vivo studies, CpG-free pDNA expressed a significantly lower level of luciferase than CpG-rich pDNA in several human cell lines. By comparing novel CpG-free pDNA carrying CpG-free GFP (pZGFP: 0 CpG) to CpG-rich GFP (pRGFP: 60 CpGs), we further showed that the discrepancy was not influenced by external factors such as gene transfer agent, cell species, cell type, and cytotoxicity. Moreover, pZGFP exhibited reduced expression despite having equal gene dosage as pRGFP. Analysis of mRNA distribution revealed that the mRNA export of pZGFP and pRGFP was similar; however, the steady state mRNA level of pZGFP was significantly lower. Upon further investigation, we found that the CpG-free transgene in non-integrating CpG-free pDNA backbone acquired increased nucleosome enrichment as compared with CpG-rich transgene, which may explain the observed reduced level of steady state mRNA. Our findings suggest that nucleosome enrichment could regulate non-integrating CpG-free pDNA expression and has implications on pDNA design.

scholarly journals Induction and repression of the urea amidolyase gene in Saccharomyces cerevisiae.

1986 ◽  
Vol 6 (11) ◽  
pp. 3954-3964 ◽  
Author(s):  
F S Genbauffe ◽  
T G Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Steady State ◽  
Normal Control ◽  
Catabolite Repression ◽  
Gene Products ◽  
Nitrogen Catabolite Repression ◽  
Wild Type ◽  
Recombinant Plasmids ◽  
Control Pattern ◽  
Steady State Levels

The DUR1,2 gene from Saccharomyces cerevisiae has been isolated on recombinant plasmids along with all DNA between the DUR1,2 and MET8 loci. DUR1,2 was found to encode a 5.7-kilobase transcript, which is consistent with our earlier suggestion that the DUR1 and DUR2 loci are two domains of a single multifunctional gene. Steady-state levels of the DUR1,2 transcript responded to induction and nitrogen catabolite repression in the same way as urea amidolyase activity. dal81 mutants (grown with inducer) contained barely detectable amounts of DUR1,2 RNA, whereas dal80 mutants (grown without inducer) contained the same amount as a wild-type induced culture. These observations support our earlier hypothesis that DUR1,2 is transcriptionally regulated, with control being mediated by the DAL80 and DAL81 gene products. We cloned the DUR1,2-Oh mutation and found it to be a Ty insertion near sequences required for complementation of dur1,2 mutations. The ROAM phenotype of the DUR1,2-Oh mutation is sharply different from that of cis-dominant, DUR80 mutations, which enhance DUR1,2 expression but do not affect the normal control pattern of the gene. There is evidence that DUR80 mutations may also be Ty insertions, which generate phenotypes that are different from those in DUR1,2-Oh mutations.

Role of STE genes in the mating factor signaling pathway mediated by GPA1 in Saccharomyces cerevisiae

1988 ◽  
Vol 8 (9) ◽  
pp. 3777-3783
Author(s):  
N Nakayama ◽  
Y Kaziro ◽  
K Arai ◽  
K Matsumoto
Keyword(s):  
Steady State ◽  
Signaling Pathway ◽  
State Level ◽  
G1 Arrest ◽  
Gene Products ◽  
Mating Efficiency ◽  
Protein Functions ◽  
Steady State Levels ◽  
Mating Factor

The ste mutants (ste2, ste4, ste5, ste7, ste11, and ste12) are insensitive to mating factors and are, therefore, sterile. Roles of the STE gene products in the GPA1-mediated mating factor signaling pathway were studied by using ste gpa1 double mutants. Mating efficiency of a ste2 mutant defective in the alpha-factor receptor increased 1,000-fold in a gpa1 background, while G1 arrest and aberrant morphology (shmoo) caused by gpa1 were not suppressed by ste2. Furthermore, the steady-state level of the FUS1 transcript, which normally increases in response to mating factors, was also elevated when the GPA1 function was impaired. These results suggest that the GPA1 protein functions downstream of the STE2 receptor. Conversely, the sterility of ste4, ste5, ste7, ste11, and ste12 mutants was not suppressed by gpa1, but the lethal phenotype of gpa1 was suppressed by these ste mutations. Northern (RNA) blotting analysis revealed that the ste7, ste11, and ste12 mutations caused reductions of 50 to 70% in the steady-state levels of the GPA1 transcript, while ste4 had a slight effect and ste5 had no effect. This implies that the suppression by ste7, ste11, and ste12 could be due to reduced syntheses of additional components, including an effector, and that suppression by ste4 and ste5 may result from direct effects on the signaling pathway. The STE4, STE5, STE7, STE11, and STE12 products, therefore, appear to specify components of the signal transduction machinery, directly or indirectly, which function together with or downstream of GPA1.

Induction and repression of the urea amidolyase gene in Saccharomyces cerevisiae

1986 ◽  
Vol 6 (11) ◽  
pp. 3954-3964
Author(s):  
F S Genbauffe ◽  
T G Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Steady State ◽  
Normal Control ◽  
Catabolite Repression ◽  
Gene Products ◽  
Nitrogen Catabolite Repression ◽  
Wild Type ◽  
Recombinant Plasmids ◽  
Control Pattern ◽  
Steady State Levels

The DUR1,2 gene from Saccharomyces cerevisiae has been isolated on recombinant plasmids along with all DNA between the DUR1,2 and MET8 loci. DUR1,2 was found to encode a 5.7-kilobase transcript, which is consistent with our earlier suggestion that the DUR1 and DUR2 loci are two domains of a single multifunctional gene. Steady-state levels of the DUR1,2 transcript responded to induction and nitrogen catabolite repression in the same way as urea amidolyase activity. dal81 mutants (grown with inducer) contained barely detectable amounts of DUR1,2 RNA, whereas dal80 mutants (grown without inducer) contained the same amount as a wild-type induced culture. These observations support our earlier hypothesis that DUR1,2 is transcriptionally regulated, with control being mediated by the DAL80 and DAL81 gene products. We cloned the DUR1,2-Oh mutation and found it to be a Ty insertion near sequences required for complementation of dur1,2 mutations. The ROAM phenotype of the DUR1,2-Oh mutation is sharply different from that of cis-dominant, DUR80 mutations, which enhance DUR1,2 expression but do not affect the normal control pattern of the gene. There is evidence that DUR80 mutations may also be Ty insertions, which generate phenotypes that are different from those in DUR1,2-Oh mutations.

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