STAT3 and RORγT in hyper IgE syndrome
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STAT3 and RORγT in hyper IgE syndrome
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[ID] => 553722
[post_author] => 12815
[post_date] => 2024-12-23 07:31:47
[post_date_gmt] => 2024-12-23 12:31:47
[post_content] => Practice Passage (Question 1-7)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Autosomal dominant hyper IgE syndrome (AD-HIES), a severe immunodeficiency disorder, is caused by a heterozygous mutation in the gene coding for the transcription factor signal transducer and activator of transcription 3 (STAT3). In healthy individuals, STAT3 resides in the cytoplasm and is phosphorylated by receptors in the cell membrane after binding of extracellular cytokines. The resulting activated protein, known as phospho-STAT3, binds a second phospho-STAT3 protein, and the resulting two-protein-complex (referred to as a “homodimer”) acts to initiate the transcription of many different genes, including the transcription factor retinoic acid-related orphan receptor gamma T (RORγT). RORγT controls important steps in the maturation process of T cells, and mutations affecting the STAT3 gene associated with AD-HIES manifest themselves in reduced populations of functional T cells.
In order to better understand the relationship between the transcription of STAT3 and RORγT in AD-HIES, researchers used a quantitative polymerase chain reaction assay to measure non-mutated STAT3 and RORγT messenger RNA (mRNA) levels in T cells derived from AD-HIES patients.
Figure 1 STAT3 and RORγT mRNA levels in T cells of AD-HIES patients and in healthy individuals (control), measured in relative units
Researchers also assessed RORγT and c-Maf expression in wild type and STAT3 deficient spleen cells, mesenteric lymph node (mLN) and small intenstine lamina propria (siLN) cells. c-Maf is a transcription factor that promotes RORγt expression and the differentiation of intestinal RORγt⁺ T cells. Results are shown in Figure 2.
Figure 2 Expression of RORγt (A) and c-Maf (B) in wild type (WT) and STAT3 deficient (STAT3\[^\text{CD4 KO}\]) cells
Figure 2 is from Hussein H et al (2020) Multiple Environmental Signaling Pathways Control the Differentiation of RORγ t-Expressing Regulatory T Cells. Front. Immunol.
[post_title] => STAT3 and RORγT in hyper IgE syndrome
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[post_name] => stat3-ror%ce%b3t-hyper-ige-syndrome
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[post_modified] => 2024-12-23 07:31:47
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[questions] => Array
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[0] => Array
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[quiz_unique_key] => 602779517
[question] => According to the passage, which is NOT a condition that would reduce RORγt expression or activity in a T cell?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The first paragraph explains how STAT3 is activated by membrane receptors and then functions as a transcription factor.
STAT3 activation in the cytoplasm involves phosphorylation and dimerization, according to the passage.
As a transcription factor, STAT3 must then move to the nucleus where it can activate RORγt expression.
Transcription factors like STAT3 contain nuclear localization signals that acts as tags, indicating that they should be moved to the nucleus.
The only answer choice that would NOT reduce RORγt expression (and therefore activity) in a T cell is the loss of kinase activity of STAT3. STAT3 is a transcription factor, not a kinase (enzyme that phosphorylates targets).
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Mutation of a nuclear localization signal on STAT3
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[1] => Array
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[each_answer] => B. Loss of kinase activity of STAT3
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[2] => Array
(
[each_answer] => C. Reduced STAT3 dimerization
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[3] => Array
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[each_answer] => D. Reduced STAT3 phosphorylation
)
)
)
[1] => Array
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[quiz_unique_key] => 3243476205
[question] => What is the best explanation for the difference in STAT3 levels in the AD-HIES group versus control?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
AD-HIES is caused by mutations in the STAT3 gene, not in RORγT.
In Figure 1, STAT3 mRNA levels in AD-HIES cells are half of STAT3 mRNA levels in the control.
The STAT3 mutation associated with AD-HIES is a heterozygous mutation, meaning that it affects one chromosome.
Thus, the data is consistent with STAT3 expression by both chromosomes in control and only one chromosome in AD-HIES.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Inactivating mutation of the STAT3 gene on one chromosome
)
[1] => Array
(
[each_answer] => B. Inactivating mutation of the STAT3 gene on both chromosomes
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[2] => Array
(
[each_answer] => C. Inactivating mutation of the RORγT gene on one chromosome
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[3] => Array
(
[each_answer] => D. Inactivating mutation of the RORγT gene on both chromosomes
)
)
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[2] => Array
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[quiz_unique_key] => 2187790141
[question] => An important mechanism by which mutations in protein complexes can cause disease is the so‐called “dominant‐negative effect.” This is observed in proteins that assemble into symmetric homomeric or heteromeric complexes if one mutated subunit can block the function of the wild‐type subunits, thus causing a disproportionate loss of function.
Assuming that the STAT3 mutation exhibits a dominent negative effect, what percentage of biologically active STAT3 homodimers would one expect to find in cells of AD-HIES patients as compared to healthy individuals?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
The mutation associated with AD-HIES is heterozygous, and data in figure one shows that AD-HIES cells have about 50% as much non-mutated STAT3 mRNA as control cells.
Individual STAT3 protein has to dimerize with another STAT3 protein to have the intended biological effect.
This means that you’d expect close to 75% of dimers to have at least one mutated subunit.
If STAT3 exhibits a dominant negative phenotype, you’d therefore expect only 25% of normal dimer activity in AD-HIES cells.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Cells of AD-HIES patients should have 100% as many biologically active STAT3 homodimers as cells of healthy individuals.
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[1] => Array
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[each_answer] => B. Cells of AD-HIES patients should have 75% as many biologically active STAT3 homodimers as cells of healthy individuals.
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[2] => Array
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[each_answer] => C. Cells of AD-HIES patients should have 50% as many biologically active STAT3 homodimers as cells of healthy individuals.
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[3] => Array
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[each_answer] => D. Cells of AD-HIES patients should have 25% as many biologically active STAT3 homodimers as cells of healthy individuals.
)
)
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[3] => Array
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[quiz_unique_key] => 1579828684
[question] => What distinguishes transcription factors like STAT3 from other gene regulatory proteins?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
Transcription factors are proteins that help control the activity of genes by entering the nucleus and binding to specific DNA sequences in the gene’s promoter region or enhancer elements.
Some transcription factors activate transcription of genes, while others prevent transcription of genes. The same is true for other regulatory elements.
Many other gene regulatory elements, such as enhancers, silencers, and insulators, also play important roles in gene regulation but do not bind directly to the DNA. Instead, they can influence gene expression by interacting with transcription factors and other proteins to modulate the transcriptional activity of specific genes.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Transcription factors reside permanently in the cell nucleus; other gene regulatory proteins translocate to the nucleus from the cytoplasm.
)
[1] => Array
(
[each_answer] => B. Transcription factors function only in activating transcription of a gene; other gene regulatory proteins function only in repressing transcription of a gene.
)
[2] => Array
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[each_answer] => C. Transcription factors cannot bind directly to DNA; some other gene regulatory proteins are able to bind directly to DNA.
)
[3] => Array
(
[each_answer] => D. Transcription factors are able to bind directly to DNA; many other gene regulatory proteins cannot bind directly to DNA.
)
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[4] => Array
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[quiz_unique_key] => 1498560436
[question] => Which of the following STAT3 mutations is most likely to NOT reduce mRNA levels of RORγT?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
You’re looking for a mutation that is most likely to be a silent mutation, not affecting STAT3 expression or activity and therefore not affecting RORγT expression.
Mutations in an intron would be more likely to remain silent (although they could have significant impact if they affect a splice site).
Single, double, or triple nucleotide deletions differ in their ability to cause frameshift mutations.
A single nucleotide deletion, even in an intron, would result in a frameshift, or a shift in the reading frame of the mRNA transcribed from the gene. This drastically affects the regions of the protein downstream of this mutation, in addition to the region where the deletion occurs.
However, a trinucleotide deletion (or deletion of a multiple of 3) will not affect the reading frame.
A trinucleotide deletion (deletion of 3 nucleotides) in an intron would therefore be the LEAST likely to affect STAT3 expression or activity, as long as it does not affect a splice site. It is possible that this mutation would result in the lost of 3 mRNA nucleotides that are cut out of the intron.
This deletion would have a less certain effect than it would in the DNA binding domain, where it would more certainly affect STAT3’s ability to activate RORγT expression.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Triple nucleotide deletion in the STAT3 DNA binding domain
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[1] => Array
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[each_answer] => B. Triple nucleotide deletion in a STAT3 intron-corresponding region
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[2] => Array
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[each_answer] => C. Double nucleotide deletion in a STAT3 intron-corresponding region
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[3] => Array
(
[each_answer] => D. Single nucleotide deletion affecting the STAT3 promoter
)
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[5] => Array
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[quiz_unique_key] => 3413571627
[question] => The results shown in Figure 2 best support which conclusion?
[value] => Array
(
[answer] => 1
[description] => Reason for Correct Answer:
The graphs in Figure 2 show RORγT (A) and c-Maf (B) expression for wild type cells (white bars) versus cells deficient in STAT3 (black bars).
The passage says that c-Maf is a transcription factor that promotes RORγt expression and the differentiation of intestinal RORγt⁺ T cells.
Graph B shows that c-Maf expression is retained in cells that are STAT3 deficient (and even elevated in STAT3 deficient mLN cells).
Graph A shows that, despite this, RORγT is still significantly reduced in cells that are STAT3 deficient.
This suggests that c-Maf expression alone is not sufficient to induce RORγT expression, as RORγT expression is reduced in STAT3 deficient cells, even when c-Maf levels are normal.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. A functional STAT3 protein restores RORγt expression and the differentiation of intestinal RORγt⁺ T cells, even in the absence of c-Maf expression.
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[1] => Array
(
[each_answer] => B. c-Maf alone is not sufficient to induce RORγt expression in T cells and likely cooperates with other signaling pathways.
)
[2] => Array
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[each_answer] => C. c-Maf expression is sufficient to induce RORγt expression in T-cells deficient in STAT3.
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[3] => Array
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[each_answer] => D. Expression of c-Maf reduces RORγt expression in regulatory T-cells.
)
)
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[6] => Array
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[quiz_unique_key] => 803665808
[question] => STAT3 is an 88-kDa protein with an isoelectric point of 5.9. Which of the following statements is correct?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
To estimate the length of a protein, use the approximation of 110 g/mol per amino acid.
88 kDa means 88,000 Da (equivalent to 88,000 g/mol). Therefore, the length can be estimated as 88,000/110 = 800 amino acids.
The isoelectric point (pI) of a protein is the pH at which the net charge is zero.
At pHs above the pI, the environment is less positive, and the net change of the protein is negative; at pHs below the pI, the net charge is positive.
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[answers] => Array
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[0] => Array
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[each_answer] => A. It has approximately 800 amino acids and a net positive charge at pH 7
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[1] => Array
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[each_answer] => B. It has approximately 800 amino acids and a net negative charge at pH 7
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[2] => Array
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[each_answer] => C. It has approximately 1600 amino acids and a net positive charge at pH 7
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[3] => Array
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[each_answer] => D. It has approximately 1600 amino acids and a net negative charge at pH 7
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Figure 1
Figure 2 Expression of RORγt (A) and c-Maf (B) in wild type (WT) and STAT3 deficient (STAT3
