Low-density lipoprotein receptor gene mutation analysis and structure-function correlation in an Omani arab family with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder typified by elevated low-density lipoprotein cholesterol (LDL-C) levels caused by mutations in the LDL receptor (LDLR), apolipoprotein B (ApoB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Previously, we reported a novel mutation in the exon-3 of LDLR gene, observed in a 9-year-old Omani Arab female. Here, we investigated the mode of inheritance of this mutation and 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 has been appraised in silico on the tertiary structure of LDLR. A model of the mutant LDLR has been 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.

Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure.

Proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. Mutations in the PCSK9 gene have previously been found to segregate with autosomal dominant familial hypercholesterolemia (ADFH). In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed for two patients with a clinical diagnosis of familial hypercholesterolemia where mutation in the LDL-receptor gene hasn't been excluded. One missense mutation was detected in the exon 9 PCSK9 gene in the two ADFH patients. The patients were found to be heterozygote for Ile474Val (SNP rs562556). Using an array of in silico tools, we have investigated the effect of the above mutation on different structural levels of the PCSK9 protein. Although, the mutation has already been reported in the literature for other populations, to the best of our knowledge this is the first report of a mutation in the PCSK9 gene from the Arab population, including the Omani population.

Distribution of the lactase persistence-associated variant alleles -13910* T and -13915* G among the people of Oman and Yemen.

The high prevalence of lactase persistence (LP) among the people of Saudi Arabia is associated with the -13915(*)G variant allele upstream of the lactase gene (LCT). We, therefore, examined the frequency of the commonly known LP associated SNPs among randomly collected samples from Omani and Yemeni adult populations and obtained further data on the distribution of the two most common LP-associated variants, -13910(*)T and -13915T(*)G, in the Arabian Peninsula. The DNA fragment containing all the reported LP- associated SNPs was amplified and genotyped. The frequency of the -13915(*)G allele was highest among Dhofari Arabs of southern Oman (0.72) followed by Yemeni Arabs (0.54) and Arabs of northern Oman (0.14). It was not detected in Omanis of Asian origin. The frequency of the -13910(*)T allele was extremely low in Arabs of northern and southern Oman (0.00-0.01) and Yemenis (0.002). However, it had a frequency of 0.160 among Omanis of Asian origin. Results show that the highest frequency of the LCT -13915(*)G variant allele appears to be in the south of the Arabian Peninsula with clinal decrease within the Peninsula and further out in surrounding countries.