As bases moleculares das hipercolesterolemias familiares no Brasil: o Rio Grande do Sul

Abstract

Werutsky, CA. The molecular bases of the familial hypercholesterolemia in Brazil: Rio Grande do Sul. 2006. 88 f. Thesis (Doctoral) – Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 2006. Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene (chromosome 19p13.1 – p13.3), which alter partially or totally the LDLR function. FH is also one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1/500 and 1/10, respectively. Affected individuals display high levels of LDL cholesterol, arcus corneae, tendon xanthomas and premature symptomatic coronary heart disease. The extensive heterogeneity observed in the clinical manifestation of this disorder may be explained, at least partially, by the broad spectrum of mutations identified in the LDLR gene. The present study had as the main goal the molecular characterization of the LDLR gene in patients with FH from Rio Grande do Sul (RS) State, Brazil. For this, DNA samples were obtained from 40 individuals living in five macroregions of RS, representing six different isolated populations of European ascendancy. The LDLR gene was subjected to the direct sequencing with further analysis through bioinformatics tools. Fifteen punctual mutations were identified in the LDLR gene, namely: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) and c.2243A>G (D727G) in the coding region, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11-69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T and IVS17-42A>G in the intronic region, and *52G>A, *105T>G and *141G>A in the 3’-UTR region. Of these, eight were not yet described in the literature (three situated in exons, four in introns and one in 3’UTR region). The *52G>A mutation was previously identified in FH patients from Southeast Brazil, suggesting that it can exert an important effect in the pathogenesis of FH in Brazilian patients. In relation to the macroregions of Rio Grande do Sul, Portuguese, Italian and Spanish subjects carried the highest number of mutations among the ethnic groups analyzed. Thus, the results obtained confirm the existence of a broad spectrum of mutations in the LDLR gene. The mutations in intronic regions need to be investigated in relation to its potential effect in the development of FH. Taking into account that this is the first study that had as the goal the molecular characterization of FH patients in RS, further studies aimed at elucidating the molecular bases of FH should be performed, in order to obtain the better characterization of this disease in Brazil.