Analysis of Low-Density Lipoprotein Receptor Gene Mutations in A Family with Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant hereditary disease, mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. It is characterized by severely elevated LDL cholesterol (LDL-C) levels, cutaneous xanthomatosis, and premature coronary heart disease.Materials and Methods: Whole exome sequencing of the proband with familial hypercholesterolemia was performed to identify the target gene and screen for suspicious pathogenic mutations. Sanger sequencing of family members was conducted to analyze family genetic-phenotypic associations. In addition, the changes in the structure and function of mutant LDLR were predicted using biological information analysis.Results: Next Generation Sequencing revealed that the proband carried two heterozygous missense point mutations c.G1027A (p.G343S) and c.G1879A (p.A627T) in LDLR (NM_000527), which could lead to FH syndrome. In this pedigree, the proband and her brother with hypercholesterolemia and xanthelasma carried the compound heterozygous mutations p.G343S and p.A627T. Her father, children, and nephew carried the p.G343S mutation, and her mother and niece carried the p.A627T mutation. The total cholesterol (TC) of a compound heterozygote was 20.50–21.35 mmol/L, the cholesterol of a heterozygote was 6.52–8.81 mmol/L, and the TC of other family members without a mutation was 2.94–3.61 mmol/L. G343S and A627T had a slight effect on the protein structure of LDLR, as simulated by Chimera. In addition, Rredictprotein software predicted that G343S and A627T affected the disordered region, protein interaction binding region, and RNA binding region of the LDLR. Gly343 and Ala627 are highly conserved in mammals and play a vital role in maintaining the function of the LDLR. YinOYang 1.2 predicted that these two sites had great potential for O-GlcNac modification, and GPS 5.0 predicted that the variants modified phosphorylation. Mutations may affect protein post-translational modification, thus changing the structure, function, location, and fate of the protein.Conclusions：The mutations c.G1027A in LDLR exon 7 and c.G1879A in exon 13 may be the molecular genetic basis of FH in this family. Compared to patients with a heterozygous variant, patients with compound heterozygous variants had much higher levels of cholesterol and had xanthoma