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 Tunis ia together with a milder clinical expression than in western countries. Th e molecular basis of FH in Tunisia remains unknown. Our aim was to identify FH-causing mutations in three unrelated families (21 subjects) from the ar ea of Souassi (central Tunisia). In probands with a presentation of homozyg ous FH, the promoter and 18 exons of the low density lipoprotein (LDL)-rece ptor gene were sequenced in both orientations. A novel complex frameshift m utation was identified in exon 10, nucleotides 1477-1479 (TCT) at Serine 47 2 were replaced by an insertion of seven nucleotides (AGAGACA), producing a premature termination codon 43 amino acids downstream. Binding of I-125-la belled LDL at 4 degreesC 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, he terozygotes n = 10. All mutation carriers shared the same haplotype (7 RFLP s), suggesting that they had a common ancestor. Despite high plasma LDL lev els (m = 16.0 +/- 3.0 mmol/l) and extravascular cholesterol deposits, most homozygotes were diagnosed after puberty and had a delayed onset of cardiov ascular complications. Moreover, most heterozygotes were free of clinical s igns and had plasma LDL cholesterol in the normal range (4.7 +/- 1.3 mmol/l ) without taking any lipid-lowering medication. This mild clinical phenotyp e which contrasted with the severity of the mutation, could not be explaine d by specific apolipoprotein E or lipoprotein lipase alleles. (C) 2001 Else vier Science Ireland Ltd. All rights reserved.