Genetic and phenotypic 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 caused, in the majority of patients, by mutations in the low density lipoprotein receptor (LDLR) gene. We characterize the mutations of the LDLR gene in 91 patients (aged 4-77 years) with clinical definitions of possible (N=7), probable (N=13) or certain (N=71) FH. Plasma LDL-C level ranged from 168 to 526 mg/dl. LDLR defects were detected in 87patients, in various regions of the gene with 1% in the signal sequence, 29% in the LDL binding domain (exons 2-6), 62% in the EGF precursor homology domain (exons 7-14) and 8% in the membrane spanning region (exons 16-17). Three patients were found homozygous for the mutations V523M, c.2312-3C>A and for the synonymous mutation G207G. One patient was compound heterozygous and 2 were double heterozygous. The most common mutations (G549D,G592E) were detected in 3 or more unrelated patients. Nonsense mutations accounted for 9.8%, missense for 51.7% and frame-shift mutations for 10.9%. We found one“in frame” deletion, 16 (18.4%) splicing mutations, and 6 (6.9%) large deletions . 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. Future analyses will be performed on genotype-negative patients to investigate other mutations involved in the development of the FH phenotype.