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?

Key Concepts

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.

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.

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.