Genetic characterization of LDL-receptor in patients with a clinical diagnosis of familial hypercholesterolemia: two novel mutations

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism. In the majority of patients, FH is caused by mutations in the gene encoding the low density lipoprotein receptor (LDLR). Aim of the present study was the characterization of mutations of the LDLR gene in 65patients with clinical definitions of possible (N=5), probable (N=2) or certain (N=58) FH. Patients were aged between 9 and81 years. Plasma LDL cholesterol (LDL-C) level ranged from 168 to 488 mg/dl. LDLR defects were detected in 57 patients, in various regions of the gene with 26% in the LDL binding domain (exons 2-6), 65% in the EGF precursor homology domain (exons 7-14) and 9% in the membrane spanning region (exons 16-17). Two patients were found homozygous for the described mutations V523M and c.2312-3C>A. The most common mutations (E288X, V523M, G549D) were detected in 3 or more unrelated patients. Nonsense mutations accounted for 5.3%, missense for 64.9% and frame-shift mutations for 12.3%. We found one “in frame” deletion (I624del) and 9 (15.8%) intronic mutations. Two heterozygous mutations were not described before. One of these is a duplication of the nucleotide in 1125 position which causes a frame-shift, ending in a stop at position 5 (p.K376Qfs*5) and one concerns a deletion of an adenine in intron 10 (c.1587-2delA). All genotypes do not significantly differ in plasmatic LDL-C level. Tendon xanthomata were present in 72 % of genetically defined FH. Future analyses will be performed on genotype-negative patients to investigate other mutations involved in the development of the FH phenotype (i.e. apoB100, PCSK9,ARH).