Identification of variants in exon 4 of the LDLR gene and assessment of their effects on the produced proteins in saudi women with metabolic syndrome.

BACKGROUND: Genetic factors might influence metabolic syndrome (MetS) or any of its components. It was postulated that low density lipoprotein receptor (LDLR) gene variants could play a role in cholesterol hemostasis and the development of MetS. However, the causal-effect relationship between such variants and the development of MetS is not clearly identified or even studied before in Saudi Arabian women. This study aims to identify the variants of LDLR exon-4 in Saudi Arabian women with MetS in comparison to healthy women and to assess the expected effect of amino acids alterations on the structure and functions of the LDLR proteins. A total of 208 female Saudi patients with MetS and 104 controls were included in the study. The exon 4 of LDLR gene was studied by DNA sequencing (Sanger) and structural analysis was performed using Project HOPE software. RESULTS: Four variants were identified; 2 were missense variants (2.4%; 5/208): (p.D172N and p.D178N) and 2 were nonsense variants (stop gained) (1.44%; 3/208): (p.E140* and p.L135*). Structural analysis of the expected effects of such variants revealed that they might disrupt their interactions with other proteins or biomolecules, additionally, the nonsense variants via expressing a stop codon, these will produce a truncated protein resulting in a defective function of LDL receptor. CONCLUSIONS: Four variants in the LDLR gene, exon 4 (2 missense and 2 nonsense variants) have been identified and their expected structural effects were assessed in Saudi Arabian women with MetS in Makkah region.