A novel splice site mutation of the LDL receptor gene in a Tunisian hypercholesterolemic family

Background Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease caused by mutations in either the low-density lipoprotein receptor, the apolipoprotein B or the proprotein convertase subtilisin/kexin type 9 genes. It is characterized by a high concentration of low-density lipoprotein (LDL), which frequently gives rise to premature coronary disease. In this study, we report a novel splice site mutation of the LDL receptor gene in a Tunisian family. Methods Seven patients from the family were screened for mutations in the LDLR gene and the apoB gene, using direct sequencing. RT-PCR and study on cultured skin fibroblast were realised to characterize the effect of novel mutation. Results Direct sequencing of the promoter and 18 exons reveals a G > A substitution in the splice site junction of intron 8 (c.1186 + 1 G > A). Study on cultured skin fibroblasts showed a residual activity of 10% of the LDL receptor. Reverse transcription, amplification and direct sequencing of RNA from patient's lymphocytes reveal a deletion of the final 51 bp of exon 8 preserving the reading frame. Conclusions The study identified a novel splice mutation c.1186 + 1 G > A in the LDL receptor gene. It causes the utilization of a new cryptic donor splice site 51 bp downstream from the normal site.