Two variants in exon and intron 9 of LDLR gene in Iranian familial hypercholesterolemia patients

Background and Aim : Familial Hypercholesterolemia (FH) is a disorder with autosomal dominant inheritance pattern. The main cause of FH is mutations in LDL receptor (LDLR) gene. Mutations in APOB and PCSK9 genes can also cause FH.A range of different mutations have been identified in the world population. Up to now, there have been a few reports of mutations in Iranian FH patients. Methods : In order to identify the causative LDLR variants, DNA of forty five unrelated individuals, diagnosed with FH by DLCN criteria, was extracted. The patients’ DNA were analyzed using a High-Resolution Melting method (HRM) for exon 9 along with intron/exon boundaries of LDLR gene. Samples with a shift in HRM and melting temperature curves were sequenced.Results : A missense variant (c.1246C> T, p.(R416W)) in exon 9 of LDLR was identified in a patient. A common variant (IVS9-30C> T, (rs1003723)) was recognized in 71% of the patients (22% homozygous and 49% heterozygous). In silico analyses using PolyPhen, SIFT, Splice Port and HOPE were accomplished to predict the effect of the variant p.(R416W) on the protein structure and IVS9-30C> T on splice site and branch point. p.(R416W) was proved to have damaging effect while IVS9-30C> T did not produce any effect. Conclusion : In conclusion due to the limitation of investigated region in LDLR gene sequence (just exon 9 and neighbor intronic boundaries) and being small of patients group, we found two notable nucleotide changes. However, this small step is the first one in this direction. In the future, investigation of other regions of LDLR sequence and different related genes involved in cholesterol metabolism in the patient that has missense homozygous 1246C> T would be able to make us more sure about clinical effect(s) of this mutation on LDLR function. Although, IVS9-30C> T is found to has no effect in splice site and branch point, the fact that this variant is located on stem loop of a new ncRNA (MIR6886) may open a new door for further investigations.

کلیدواژه ها:

Familial hypercholesterolemia ، high-resolution melting ، Iran ، low-density lipoprotein receptor ، missense mutation