Abstract 395: Identification and Characterization of a Novel Mutation in the Low-Density Lipoprotein Receptor Gene in an Omani Arab Family With Familial Hypercholesterolemia

Abstract

Autosomal dominant familial hypercholesterolemia (FH) is caused due to mutations in the low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B (ApoB) genes. Little is known regarding its prevalence in the Arab population, which not only exhibits relative genetic homogeneity, but also has a lengthy tradition of consanguinity. In this study we screened for mutations in FH associated gene in an Omani Arab family, where FH was detected in the index patients according to the Simon Broome criteria. Effect of the identified mutations on different protein structural levels was investigated in silico. The index patient (9-year-old female) was presented to the lipid clinic with eye xanthelasmata and thickening of both Achilles tendons, and showed off treatment total cholesterol of 896 mg/dL (23.2 mmol/L), low-density lipoprotein cholesterol (LDL-C) of 853 mg/dL (22.1 mmol/L), APOB of 4.5 g/L, triglyceride of 71 mg/dL (0.8 mmol/L), and high-density lipoprotein cholesterol of 0.74 mmol/L. She was treated with a combination of rosuvastatin/ezetimibe and LDL apheresis. Genetic analysis of the LDLR gene showed a homozygous frame-shift deletion mutation (272delG) at exon 3, which truncates the protein after 90 amino acid residues (versus ~840 amino acids in the wild-type). The mode of inheritance of this novel mutation was also studied to construct a family tree. Additionally it was also confirmed that FH in this family is due to mutation only in the LDLR and not PCSK9 and ApoB genes. Further, the effect of the mutation was also appraised in silico on the tertiary structure of LDLR. A model of the mutant LDLR was constructed using the coordinates of the wild-type LDLR extracellular domain. Based on the model, we present a mechanistic justification behind the observed detrimental effect of the mutation on LDL-C levels.