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Ch. 17+18 - Transcriptional Regulation in Eukaryotes
Chapter 17, Problem 26

Mutations in the low-density lipoprotein receptor (LDLR) gene are a primary cause of familial hypercholesterolemia. One such mutation is a SNP in exon 12 of the LDLR. In premenopausal women, but not in men or postmenopausal women, this SNP leads to skipping of exon 12 and production of a truncated nonfunctional protein. It is hypothesized that this SNP compromises a splice enhancer [Zhu et al. (2007). Hum Mol Genet. 16:1765–1772]. What are some possible ways in which this SNP can lead to this defect, but only in premenopausal women?

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1
Understand the role of the LDLR gene and its importance in cholesterol metabolism. The LDLR gene encodes the low-density lipoprotein receptor, which is crucial for removing LDL cholesterol from the bloodstream.
Recognize that the SNP in exon 12 affects splicing, specifically leading to exon skipping. Exon skipping can result in a truncated protein that is nonfunctional, as it lacks essential domains encoded by the skipped exon.
Consider the role of splice enhancers, which are sequences that promote the inclusion of an exon during mRNA splicing. The SNP may disrupt a splice enhancer, leading to exon 12 being skipped during mRNA processing.
Explore why this effect is specific to premenopausal women. Hormonal differences, such as estrogen levels, could influence the splicing machinery or the expression of splicing factors, making premenopausal women more susceptible to the effects of the SNP.
Investigate the potential involvement of estrogen-responsive elements or splicing factors that are differentially expressed in premenopausal women. These factors might interact with the splice enhancer or the splicing machinery, leading to the observed phenotype.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Single Nucleotide Polymorphism (SNP)

A Single Nucleotide Polymorphism (SNP) is a variation at a single position in a DNA sequence among individuals. SNPs can affect gene function and expression, potentially leading to diseases. In the context of the LDLR gene, the SNP in exon 12 alters the splicing process, which can result in a nonfunctional protein, particularly in specific populations such as premenopausal women.
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Alternative Splicing

Alternative splicing is a process by which a single gene can produce multiple protein isoforms by including or excluding certain exons during mRNA processing. This mechanism allows for greater diversity in protein function. The skipping of exon 12 due to the SNP in the LDLR gene exemplifies how alternative splicing can lead to the production of a truncated protein, impacting its functionality.
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Sex Hormones and Gene Expression

Sex hormones, such as estrogen, can influence gene expression and splicing mechanisms in a sex-specific manner. In premenopausal women, estrogen may enhance the activity of splice enhancers, making them more susceptible to the effects of the SNP in the LDLR gene. This hormonal influence could explain why the mutation leads to exon skipping and a nonfunctional protein specifically in this demographic.
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Related Practice
Textbook Question

Regulation of the lac operon in E. coli (see Chapter 16) and regulation of the GAL system in yeast are analogous in that they both serve to adapt cells to growth on different carbon sources. However, the transcriptional changes are accomplished very differently. Consider the conceptual similarities and differences as you address the following.

Compare and contrast the cis-regulatory elements of the lac operon and GAL gene system.

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Textbook Question

Regulation of the lac operon in E. coli (see Chapter 16) and regulation of the GAL system in yeast are analogous in that they both serve to adapt cells to growth on different carbon sources. However, the transcriptional changes are accomplished very differently. Consider the conceptual similarities and differences as you address the following.

Compare and contrast how these two systems are negatively regulated such that they are downregulated in the presence of glucose.

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Textbook Question

Incorrectly spliced RNAs often lead to human pathologies. Scientists have examined cancer cells for splice-specific changes and found that many of the changes disrupt tumor-suppressor gene function [Xu and Lee (2003). Nucl. Acids Res. 31:5635–5643]. In general, what would be the effects of splicing changes on these RNAs and the function of tumor-suppressor gene function? How might loss of splicing specificity be associated with cancer?

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Textbook Question

During an examination of the genomic sequences surrounding the human β-globin gene, you discover a region of DNA that bears sequence resemblance to the glucocorticoid response element (GRE) of the human metallothionein IIA (hMTIIA) gene. Describe experiments that you would design to test (1) whether this sequence was necessary for accurate β-globin gene expression and (2) whether this sequence acted in the same way as the hMTIIA gene's GRE.

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Textbook Question

RNA helicases are a class of proteins that bind mRNAs and influence their secondary structures and interactions with other proteins. RNA helicases have been implicated in many steps of RNA regulation such as splicing, decay, and translation. Why might these enzymes be so ubiquitously required for RNA regulation?

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Textbook Question

Marine stickleback fish have pelvic fins with long spines that provide protection from larger predatory fish. Some stickleback fish were trapped in lakes and have adapted to life in a different environment. Many lake populations of stickleback fish lack pelvic fins. Shapiro et al. (2004) (Nature 428:717.723) mapped the mutation associated with the loss of pelvic fins to the Pitx1 locus, a gene expressed in pelvic fins, the pituitary gland, and the jaw. However, the coding sequence of the Pitx1 gene is identical in marine and lake stickleback [Chan et al. (2010). Science 327:5963,302–305]. Moreover, when the Pitx1 coding region is deleted, the fish die with defects in the pituitary gland and the jaw, and they lack pelvic fins. Explain how a mutation near, but outside of, the coding region of Pitx1 may cause a loss of pelvic fins without pleiotropic effects on the pituitary gland and jaw.

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