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

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 (L...

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Bibliographic Details
Published in:Clinica chimica acta 2008-06, Vol.392 (1), p.25-29
Main Authors: Jelassi, A., Najah, M., Jguirim, I., Maatouk, F., Lestavel, S., Laroussi, O.S., Rouis, M., Boileau, C., Rabès, J.P., Varret, M., Slimane, M.N.
Format: Article
Language:English
Subjects:
Adult
Aged
Apolipoproteins B - genetics
Apolipoproteins B - metabolism
Cells, Cultured
Familial hypercholesterolemia
Family
Female
Fibroblasts - metabolism
Humans
Hypercholesterolemia - blood
Hypercholesterolemia - genetics
Introns
Low-density lipoprotein receptor
Male
Middle Aged
Mutation
New splice site mutation
Receptors, LDL - genetics
Receptors, LDL - metabolism
RNA Splice Sites
Tunisia
Tunisian
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Summary: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. 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. 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. 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.
ISSN:0009-8981
1873-3492
DOI:10.1016/j.cca.2008.02.019