Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia
Autor: | Monirah Albabtain, Dalal Al Ammari, Abdellatif Bouazzaoui, Hussam Karrar, Mohammad Athar, Fahad Alnouri, Faisal A. Al-Allaf, Mohiuddin M. Taher, Zainularifeen Abduljaleel |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Proband Heterozygote Heredity Protein Conformation DNA Mutational Analysis Mutation Missense Coronary Artery Disease Familial hypercholesterolemia Molecular Dynamics Simulation Biology Risk Assessment Severity of Illness Index Frameshift mutation Hyperlipoproteinemia Type II Structure-Activity Relationship 03 medical and health sciences Predictive Value of Tests Risk Factors medicine Humans Missense mutation Genetic Predisposition to Disease Genetic Testing Frameshift Mutation Gene Adaptor Proteins Signal Transducing Genetics Homozygote High-Throughput Nucleotide Sequencing Heterozygote advantage Cholesterol LDL Middle Aged medicine.disease Phenotype Pedigree 030104 developmental biology Receptors LDL LDL receptor Female Cardiology and Cardiovascular Medicine Biomarkers |
Zdroj: | Atherosclerosis. 277:425-433 |
ISSN: | 0021-9150 |
Popis: | Background and aims Familial hypercholesterolemia (FH) is a predominantly autosomal dominant hereditary disorder with significant potential for expansion of coronary artery disease. Methods To identify candidate variant/s in FH phenotype implicated genes, next-generation sequencing was performed using a targeted customized gene panel. Results We recognized a 45-year-old Saudi female FH patient with double variants in the LDLR [c.1255 T > G, p.(Y419D)] and LDLRAP1 genes [c.604_605delTCinsA, p.(S202Tfs*2)]. The proband was found to be homozygous for the LDLR variant and heterozygous for the LDLRAP1 variant. Three of the proband's children were found to be double heterozygous for the LDLR/LDLRAP1 gene variant. While her other three children were heterozygous for the same single LDLR variant. Both variants were not previously reported. The variants segregation pattern correlated with the clinical picture and with the patient's lipid profile. FH severity was greater in the proband while her children did not show any clinical manifestations. The missense variant p.(Y419D) was found to be deleterious and clinically significant based on prediction identified by PolyPhen-2 and Proven. Molecular dynamics simulation was used to further analyze the effect of the variant p.(Y419D) on the structure and function of the LDLR protein. The secondary structure was investigated, as well as the solvent accessibility and stabilizing residues. The frameshift variant of the LDLRAP1 gene results in a truncated peptide that could affect the cellular internalization of LDLR/LDL complex. Conclusions The finding of the combined variants in LDLR/LDLRAP1 genes triggering a severe FH phenotype is essential to elaborate the spectrum of variants causing FH and to understand the genotype-phenotype correlation. |
Databáze: | OpenAIRE |
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