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
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
Externí odkaz: