Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the LDLR and PCSK9 genes, as well as a part of the APOB gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon–intron boundaries of the LDLR and PCSK9 genes and the main parts of their introns, together with exon 26 of the APOB gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs∗72) in LDLR and a double mutation (p.Asp172His and p.Ala53Val) in both LDLR and PCSK9 genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C > G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of LDLR and PCSK9 variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.

In vitro assessment of the pathogenicity of the LDLR c.2160delC variant in familial hypercholesterolemia

“…LDLR mutations can be classified into five types based on their function and synthesis, including type 1 dysfunction of LDLR synthesis (nonsense mutation and splicing mutation); type 2 defect of LDLR trafficking to the cell membrane (generally in ligand-binding domains or EGF precursor homologous domains); type 3 impaired LDL binding (mainly in ligand-binding domain and homologous domain of EGF precursors); type 4 reduced capacity for receptor-mediated endocytosis (mainly in transmembrane domains and cytoplasmic domains); and type 5 diminished LDLR recycling capacity (mainly in homologous domain of EGF precursor) [ 34 , 35 ]. The new variant reported in the present study is located at LDLR exon 15, corresponding to the O-linked sugar domain [ 36 ]. A previous study similarly found that the O-linked sugar domain might regulate LDLR stability or LDLR release from cells [ 37 ].…”

Familial Hypercholesterolaemia as a Predisposing Factor for Atherosclerosis

“…The influence of various FH-causing mutations on the disease severity and CVD risk is not clear. Among carriers of LDLR mutations, the ones carrying LDLR-negative mutations were found to be more vulnerable to premature atherosclerosis development than patients with LDLR-defective mutations [ 2 ].…”

“…Although, in some regions, founder effects can affect the statistics; on average, between 0.17% to 0.5% of people suffer from a heterozygous form of the disease. Research shows that homozygous hypercholesterolaemia, which was said to affect 0.001% of the population, turns out to be around three times more common [ 2 ].…”

Associations between low serum levels of ANRIL and some common gene SNPs in Iranian patients with premature coronary artery disease

“…Early diagnosis of CAD is crucial in Iran due to the increasing incidence of premature CAD in recent years. Sedentary lifestyles, familial CAD, type 2 diabetes (T2D), hyperlipidemia, and smoking are the most frequently correlated risk factors, although the precise involvement of genetic susceptibility factors should not be underestimated in population-based studies 22 , 23 .…”