The Lebanese mutation as an important cause of familial hypercholesterolemia in Brazil

Abstract

Familial hypercholesterolemia (FH) is a common autosomal disorder that affects about one in 500 individuals in most Western populations and is caused by a defect in the low-density-lipoprotein receptor (LDLr) gene. In this report we determined the molecular basis of FH in 59 patients from 31 unrelated Brazilian families. All patients were screened for the Lebanese mutation, gross abnormalities of the LDLr gene, and the point mutation in the codon 3500 of the apolipoprotein B-100 gene. None of the 59 patients presented the apoB-3500 mutation, suggesting that familial defective ApoB-100 (FDB) is not a major cause of inherited hypercholesterolemia in Brazil. A novel 4-kb deletion in the LDLr gene, spanning from intron 12 to intron 14, was characterized in one family. Both 5' and 3' breakpoint regions were located within Alu repetitive sequences, which are probably involved in the crossing over that generated this rearrangement. The Lebanese mutation was detected in 9 of the 31 families, always associated with Arab ancestry. Two different LDLr gene haplotypes were demonstrated in association with the Lebanese mutation. Our results suggest the importance of the Lebanese mutation as a cause of FH in Brazil and by analogy the same feature may be expected in other countries with a large Arab population, such as North American and Western European countries. Correspondence

The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

“…A founder effect was suspected and was believed to explain the extraordinary high incidence of hypercholesterolemia in the country. This so-called "Lebanese allele" was also reported in FH patients of Lebanese origin either in neighboring countries [Syria (Lehrman et al 1987), Cyprus , Israel (Christian Arab families) (Reshef et al 1996) and Greece ], or worldwide due to the important Lebanese immigration [Brazil (Figueiredo et al 1992;Alberto et al 1999), Canada (Hsia et al 1996), United Kingdom (Day et al 1997), France (Nissen et al 1998), South Africa (Callis et al 1998)]. However, no thorough population study had till this date been performed in Lebanon.…”

Research Article Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil.

“…Based on our data and on the previous data from Figueiredo et al (1992) and Alberto et al (1999), we are encouraged to affirm that mutations IVS7+10G>C and C681X may be a cause of FH in the Southeast Brazil and should be at first investigated when considering the clinical hypothesis of FH in this region. Furthermore, if considering an expanded panel of mutations, six mutations (Table 3) should be screened for the FH diagnosis among patients in this same region.…”

“…The most frequent mutation causing FH among our cohort was the putative splicing mutation IVS7+10G>C (42%), followed by the mutations C681X (9%), D178Y (4%), and S326C (2%) ( Table 3). The articles of Figueiredo et al (1992) and Alberto et al (1999) are considered the first studies that reported the molecular characterization of FH caused by a deficiency of the LDLR gene in Brazil. These studies reported two mutations as the cause of FH in their patients: a 4-kb deletion involving exons 13 and 14 of the LDLR gene and the mutation C681X that creates a stop codon and the production of a truncated protein or a protein partially translated.…”

“…The study of the molecular defects of the LDLR in Brazil was initiated by Figueiredo et al (1992) and Alberto et al (1999). These researchers identified the molecular basis of FH in 16 families.…”

The panorama of familial hypercholesterolemia in Latin America: a systematic review

“…This was the first report of this mutation in a non-Arab population, indicating an important contribution of this ethnic group to FH in Brazil. Alberto et al (22) studied 59 FH subjects from the same region of Brazil and confirmed the presence of the Lebanese allele in 30% of the cases. Several years later, Salazar et al (24) discovered seven novel LDLR mutations in families living in Sao Paolo; however, the Lebanese mutation was not found.…”