The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with premature cardiovascular disease (CVD). Mutations in the LDLR, APOB, and PCSK9 genes are known to cause FH. In this study, we analysed the genetic spectrum of the disease in subjects from the Iranian population with a clinical diagnosis of FH. Samples were collected from 16 children and family members from five different cities of Iran. Probands were screened for mutations in the LDLR, APOB, and PCSK9 genes using next generation sequencing, with results confirmed by Sanger sequencing. The likely pathology of identified variants was examined using in silico tools. Of the probands, 14 had a clinical diagnosis of homozygous FH and two of heterozygous FH. No mutations were found in either APOB or PCSK9, but nine probands were homozygous for seven different LDLR mutations, with p.(Trp577Arg) occurring in three and p.Val806Glyfs*11 occurring in two patients. Two mutations were novel: p.(Leu479Gln) and p.(Glu668*). Seven probands with a clinical diagnosis of FH were mutation negative. This pilot study, integrating clinical and molecular-based techniques, begins to elucidate the FH heterogeneity and the mutation spectrum in the Iranian population. Such information is important for future disease management and cost savings.

Genetics, Screening, and Treatment of Familial Hypercholesterolemia: Experience Gained From the Implementation of the Vietnam Familial Hypercholesterolemia Registry

“…This frameshift variant results in the loss of 18 amino acids and addition of 86 amino acids at the C-terminal of the LDLR. In general, simultaneous occurrence of both the previously reported variants and the novel variant detected in this study suggest a broad spectrum of mutations and high heterogeneity of FH in the Vietnamese population, which is similar to that observed in other countries ( Jiang et al, 2015 ; Fairoozy et al, 2017 ).…”

Pulse wave velocity as a measure of arterial stiffness in patients with familial hypercholesterolemia: a systematic review and meta-analysis

“…FH is, in more than 90% of cases, caused by loss-of-function (LOF) mutations in the gene encoding LDL receptor (LDLR), which have as a consequence a decreased cellular uptake of LDL particles and therefore significantly elevated plasma LDL-C concentrations [13]. Currently more than 1700 such mutations have been documented [14, 15]. However, mutations of other genes related to apolipoprotein B that affect the LDLR-binding domain of apolipoprotein B as the most important apolipoprotein for LDL particles’ uptake, and the gain-of-function (GOF) mutations of proprotein convertase subtilisin/kexin9 (PCSK9) – a serine protease essential for LDLR recycling – have also been identified and they result in an identical phenotype as patients with LDLR mutations [2, 16].…”

Molecular mechanisms and genetic regulation in atherosclerosis

“…The DNA base transversion leads to the conversion of amino acid arginine (Arg) to glycine (Gln), cysteine (Cys) to Arg, aspartic acid (Asp) to asparagine (Asn), and Asp to glycine (Gly) in the binding domain of LDL leading to LDLR dysfunction [ 37 ]. The adhesion of LDL and LDLR and subsequent uptake and removal LDL from the circulation is reduced, thus promoting plasma retention of LDL, ox-LDL, vascular inflammation and AS plaque development [ 38 , 39 ]. Clinical studies indicate that the missense mutations in proprotein convertase substilisin/kexin type 9 (PCSK9), a gene that activate other serine protease in the secretory pathway, causes severe FH, suggesting additional factors beyond the loss-of-function mutation in the LDLR and apolopoprotein B (apoB) genes are of importance.…”