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?

Verified step by step guidance

1. Understand the role of splice enhancers: Splice enhancers are sequences within exons that promote correct splicing by recruiting specific splicing factors. A mutation in such a region can disrupt the binding of these factors, leading to exon skipping.
2. Consider the effect of the SNP on the splice enhancer: The SNP in exon 12 may alter the sequence of the splice enhancer, reducing or abolishing the binding affinity of splicing activators necessary for inclusion of exon 12 during mRNA processing.
3. Explore the influence of hormonal environment: Since the exon skipping occurs only in premenopausal women, hypothesize that estrogen or other hormones present at higher levels before menopause modulate the expression or activity of splicing factors that interact with the splice enhancer.
4. Examine tissue- or condition-specific splicing factors: Identify splicing factors whose expression or function is regulated by hormonal status and that specifically recognize the splice enhancer sequence affected by the SNP, explaining why exon skipping is limited to premenopausal women.
5. Integrate the molecular and physiological context: Conclude that the SNP disrupts a splice enhancer sequence that requires hormone-dependent splicing factors for proper exon inclusion, leading to exon 12 skipping and truncated protein production only in the hormonal milieu of premenopausal women.

Key Concepts

Splice Enhancers and Alternative Splicing

Splice enhancers are sequences within exons that promote correct splicing by recruiting splicing factors. Mutations in these regions can disrupt normal exon recognition, leading to exon skipping or inclusion errors. Alternative splicing allows a single gene to produce multiple protein isoforms, and its regulation can be tissue- or condition-specific.

Single Nucleotide Polymorphisms (SNPs) and Their Functional Impact

SNPs are single base changes in DNA that can affect gene function if they occur in critical regions like splice sites or enhancers. A SNP in an exon can alter binding sites for splicing factors, causing aberrant splicing. The functional impact of SNPs can vary depending on cellular context or regulatory environment.

Hormonal Regulation of Splicing in Premenopausal Women

Hormones such as estrogen, which are higher in premenopausal women, can influence splicing factor expression or activity. This hormonal environment may modulate spliceosome components or enhancer binding, explaining why the SNP-induced exon skipping occurs only in premenopausal women and not in men or postmenopausal women.