Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a novel mutation in intron 14, which activates a cryptic splice site

作者：Kulseth Mari Ann^*; Berge Knut Erik; Bogsrud Martin Proven; Leren Trond P

来源：Journal of Human Genetics, 2010, 55(10): 676-680.

DOI：10.1038/jhg.2010.87

• c.2140+86
• cryptic splice site
• familial hypercholesterolemia
• FH
• LDLR

Familial hypercholesterolemia (FH) is caused by a defective low-density lipoprotein receptor (LDLR), and >1000 mutations in LDLR have been identified. However, in some patients with clinically defined FH, no mutation can be detected within the exons and adjacent intronic segments of the LDLR. We have analyzed RNA extracted from blood samples of patients with clinically defined FH and identified an aberrantly spliced mRNA containing an 81-bp insert from intron 14. The aberrant splicing was caused by a novel intronic mutation, c.2140+86C>G, which activated a cryptic splice site. Although the cryptic splice site does not completely surpass the normal splice site, the mutation was found to cosegregate with high cholesterol levels in a family, which supports the notion that c.2140+86C>G causes FH. The insertion of 81 bp in LDLR mRNA encodes an in-frame insertion of 27 amino acids in the LDLR. However, the insertion was found to hamper LDLR activity by preventing the receptor from leaving the endoplasmic reticulum, probably because of misfolding of the protein. In patients with clinically defined hypercholesterolemia, despite normal results from sequencing of exonic regions of the LDLR gene, characterization of the LDLR mRNA might identify the underlying genetic defect. Journal of Human Genetics (2010) 55, 676-680; doi:10.1038/jhg.2010.87; published online 12 August 2010

• 出版日期2010-10