Fh-Souassi: a founder frameshift mutation in exon 10 of the LDL-receptor gene, associated with a mild phenotype in Tunisian families.
Familial hypercholesterolemia (FH) has a higher prevalence in central Tunisia together with a milder clinical expression than in western countries. The molecular basis of FH in Tunisia remains unknown. Our aim was to identify FH-causing mutations in three unrelated families (21 subjects) from the area of Souassi (central Tunisia). In probands with a presentation of homozygous FH, the promoter and 18 exons of the low density lipoprotein (LDL)-receptor gene were sequenced in both orientations. A novel complex frameshift mutation was identified in exon 10, nucleotides 1477-1479 (TCT) at Serine 472 were replaced by an insertion of seven nucleotides (AGAGACA), producing a premature termination codon 43 amino acids downstream. Binding of 125I-labelled LDL at 4 degrees C to cultured fibroblasts from two probands showed <2% normal LDL-receptor activity. AvaII digestion of PCR amplified genomic DNA identified this unique mutation in all families; homozygotes n=11, heterozygotes n=10. All mutation carriers shared the same haplotype (7 RFLPs), suggesting that they had a common ancestor. Despite high plasma LDL levels (m=16.0+/-3.0 mmol/l) and extravascular cholesterol deposits, most homozygotes were diagnosed after puberty and had a delayed onset of cardiovascular complications. Moreover, most heterozygotes were free of clinical signs and had plasma LDL cholesterol in the normal range (4.7+/-1.3 mmol/l) without taking any lipid-lowering medication. This mild clinical phenotype which contrasted with the severity of the mutation, could not be explained by specific apolipoprotein E or lipoprotein lipase alleles.
Laboratoire de Biochimie, Faculté de Médecine de Monastir, 5019, Monastir, Tunisia. sophie.lestavel@pasteur-lille.fr
M N
MN
Slimane
S
S
Lestavel
X
X
Sun
F
F
Maatouk
A K
AK
Soutar
M H
MH
Ben Farhat
V
V
Clavey
P
P
Benlian
M
M
Hammami
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood; D005091:Exons / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D014416:Tunisia
D008078:Cholesterol, LDL; D011973:Receptors, LDL