Dataset Information

A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia.

ABSTRACT: Background:Familial hypercholesterolemia (FH) is a disorder that is inherited by autosomal dominant pattern. The main cause of FH disease is the occurrence of mutations in low-density lipoprotein receptor (LDLR) gene sequence, as well as apolipoprotein B and proprotein convertase subtilisin/kexin type 9 genes, located in the next ranks, respectively. Materials and Methods:Forty-five unrelated Iranian patients with FH were screened using a high-resolution melting (HRM) method for exon 9 along with intron/exon boundaries of LDLR gene. Samples with shift in resultant HRM curves were compared to normal ones, sequenced, and analyzed. Results:Our findings revealed a missense mutation c. 1246C>T and a known variant IVS9-30C>T (rs1003723) that was recognized in 71% of the patients (22%: homozygous and 49%: heterozygous genotypes). In silico analysis, predicted the pathological effect of the c. 1246C>T mutation in LDLR protein structure, but IVS9-30C>T variant had no predicted effect on splice site and branch point function. Conclusion:FH is a hereditary type of hypercholesterolemia that leads to premature cardiovascular disease and atherosclerosis, and early diagnosis is needed. We detected a rare missense mutation (1246C>T) and a common single nucleotide polymorphism (SNP) in the Iranian population. These reports could help in the genetic diagnosis and counseling of FH patients.

SUBMITTER: Tajamolian M

PROVIDER: S-EPMC5841003 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Rare Missense Mutation and a Polymorphism with High Frequency in <i>LDLR</i> Gene among Iranian Patients with Familial Hypercholesterolemia.

Tajamolian Masoud M Kolahdouz Parisa P Nikpour Parvaneh P Forouzannia Seyed Khalil SK Sheikhha Mohammad Hasan MH Yazd Ehsan Farashahi EF

Advanced biomedical research 20180221

<h4>Background</h4>Familial hypercholesterolemia (FH) is a disorder that is inherited by autosomal dominant pattern. The main cause of FH disease is the occurrence of mutations in low-density lipoprotein receptor (LDLR) gene sequence, as well as apolipoprotein B and proprotein convertase subtilisin/kexin type 9 genes, located in the next ranks, respectively.<h4>Materials and methods</h4>Forty-five unrelated Iranian patients with FH were screened using a high-resolution melting (HRM) method for e ...[more]

PMID: 29531935

Similar Datasets

Project description: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.

Project description:Background and aimsThe accumulation of misfolded proteins, encoded by genetic variants of functional genes leads to Endoplasmic Reticulum (ER) stress, which is a critical consequence in human disorders such as familial hypercholesterolemia, cardiovascular and hepatic diseases. In addition to the identification of ER stress as a contributing factor to pathogenicity, extensive studies on the role of oxidized Low-Density Lipoprotein (oxLDL) and its ill effects in expediting cardiovascular diseases and other metabolic comorbidities are well documented. However, the current understanding of its role in hepatic insults needs to be revised. This study elucidates the molecular mechanisms underlying the progression of oxLDL and ER stress-induced cytotoxicity in HepG2.MethodsHepG2 cells stably expressing wild-type Low-Density lipoprotein receptor (WT-LDLR) and missense variants of LDLR that are pathogenically associated with familial hypercholesterolemia were used as the in vitro models. The relative mRNA expression and protein profiles of ER stress sensors, inflammatory and apoptotic markers, together with cytotoxic assays and measurement of mitochondrial membrane potential, were carried out in HepG2 cells treated with 100 µg per ml oxLDL for 24 to 48 h. 1-way or 2-way ANOVA was used for statistical analyses of datasets.ResultsER stress responses are elicited along all three arms of the unfolded protein response (UPR), with adverse cytotoxic and inflammatory responses in oxLDL-treated conditions. Interestingly, oxLDL-treated ER-stressed HepG2 cells manifested intriguingly low expression of BiP- the master regulator of ER stress, as observed earlier by various researchers in liver biopsies of Non-Alcoholic Steatohepatitis (NASH) patients. This study shows that overexpression of BiP rescues hepatic cells from cytotoxic and inflammatory mechanisms instigated by ER stress in combination with oxLDL, along the ER and mitochondrial membrane and restores cellular homeostasis.ConclusionThe data provide interesting leads that identify patients with familial hypercholesterolemia conditions and potentially other Endoplasmic Reticulum Associated Degradation (ERAD) diseases as highly susceptible to developing hepatic insults with molecular signatures like those manifested in Non-Alcoholic Fatty Liver Disease (NAFLD) and NASH.Limitations and future perspectivesAlthough the use of HepG2 cells as the model is a major caveat of the study, the findings of this research may be used as the pilot study to expand further investigations in primary hepatocytes or iPSC- derived cellular models.

Dataset Information

A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia.

Publications

A Rare Missense Mutation and a Polymorphism with High Frequency in <i>LDLR</i> Gene among Iranian Patients with Familial Hypercholesterolemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets