The autosomal dominant form of FH is mostly due to the heterozygous and homozygous states of pathogenic variants in the low-density lipoprotein receptor ( LDLR), apolipoprotein B ( APOB), and proprotein convertase subtilisin/kexin type 9 ( PCSK9) genes. This monogenic disorder is inherited in two forms of autosomal dominant and autosomal recessive ( De Castro-Orós et al., 2010 Cuchel et al., 2014a). The current prevalence of FH is estimated to be 1:311 individuals in the general population ( Beheshti et al., 2020 Hu et al., 2020). Untreated patients carry the risk of early onset coronary artery disease (premature CAD) and the augmented risk of cardiovascular events ( Nordestgaard et al., 2013 Cuchel et al., 2014b Gidding et al., 2015 Krogh et al., 2016). 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.įamilial hypercholesterolemia (FH) is a monogenic disorder of the metabolism of low-density lipoprotein cholesterol (LDL-C) and is characterized by lifelong elevated levels of LDL particles and LDL-C arterial deposits ( Khachadurian, 1964 Brown and Goldstein, 1974). 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. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C > G ) and to cosegregate it from the affected individual in the family. 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.
The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software.
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. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. 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. 3Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, University of Montreal, Montreal, QC, Canadaįamilial 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).2Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.1Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Arman Moradi 1, Majid Maleki 2, Zahra Ghaemmaghami 2, Zahra Khajali 2, Feridoun Noohi 2, Maryam Hosseini Moghadam 2, Samira Kalyinia 2, Seyed Javad Mowla 1, Nabil G.
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