Two novel mutations of the LDL receptor gene associated with familial hypercholesterolemia in a Chinese family

Background Familial hypercholesterolemia (FH) is a type of dominant autosomal disease that causes high levels ofplasma low-density lipoprotein cholesterol(LDL-C).In the past years,molecular data related to FH were limited in China.Now,to gain more information about FH,we analyzed one proband with a severe FH phenotype as well as his relatives.Methods After the entire coding sequence and the intron-exon junctions of the low-density lipoprotein receptor (LDLR)gene were amplified using PCR,we sequenced the LDLR gene of a Chinese FH family.RT-PCR was used to detectchanges in the mRNA.Results Two novel mutations were identified in the LDLR gene of this family.One,W165X,was a G>A substitution atthe third nucleotide of codon 165.The other,IVS5-1G>A,was also a G>A substitution at the acceptor splice site of intron5.The most striking discovery is that the proband was heterozygous for W165X but homozygous for IVS5-1G>A.ThecDNA sequencing showed that the IVS5-1G>A mutation caused the insertion of 10 nucleotides,namely GCTCTCACAA,between exon 5 and exon 6.Conclusions The two nucleotide variations are thought to be the FH-causing mutations because the co-segregation ofthe mutant allele with the phenotype of FH has been shown in this Chinese family.These data show an increase in themutational spectrum of FH in China and verify a scarce mutational form in the LDLR gene.Chin Med J 2007;120(19):1694-1699