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.
Jelassi
A
A
Research Unit of Genetic and Biologic Factors of Atherosclerosis, Faculty of Medecine, Monastir, Tunisia.
Najah
M
M
Jguirim
I
I
Maatouk
F
F
Lestavel
S
S
Laroussi
O S
OS
Rouis
M
M
Boileau
C
C
Rabès
J P
JP
Varret
M
M
Slimane
M N
MN
D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005190:Family; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D022821:RNA Splice Sites; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014416:Tunisia
D001055:Apolipoproteins B; D022821:RNA Splice Sites; D011973:Receptors, LDL