中文摘要：

目的检测家族性高胆固醇血症（FH）患儿低密度脂蛋白受体（LDL-r）基因突变，分析基因型与临床表型间的关系，探讨FH的分子病理机制。方法对1名15岁男性FH患儿进行心电图、血脂、心脏及大血管彩色多普勒超声检查；进而采用降落式PCR方法扩增LDL-r基因的启动子和全部18个外显子片段，进行核苷酸序列分析。结果患儿颈动脉内一中膜厚度（IMT）增厚为0．23cm，二尖瓣中度关闭不全，中度返流。冠状动脉血流速度储备（CFVR）降低为1．57。进一步的基因分析显示，患儿第10外显子存在一纯合突变，核苷酸序列分析证实第10外显子发生trp^462→stop即纯合无义突变，其胞妹及父亲该外显子相同位点分别存在纯合及杂合突变。该突变可导致终止密码子在第462位提前出现（W462X），为致病性突变。体外实验证实，W462突变可显著降低LDL—r对LDL的结合和内吞能力。结论在临床确诊的汉族FH患者中检测到LDL-r基因致病性突变第10外显子W462X，该突变使得终止密码子在第462位提前出现，从而不能表达正常的LDL—r，并导致患者胆固醇的代谢障碍及严重的临床表型。W462X突变可能是我国汉族FH患者的突变热点。

英文摘要：

Objective To explore the molecular basis of familial hypercholesteraemia （FH） by analyzing the phenotype and genotype relationship through identify the low density liporotein receptor（ LDL - r） geoe mutation in a FH kindred. Methods A male patient of 15 years old was selected to examine the electrocardiogram, lipid. Color Doppler was used to examine heart and great vessels. The promoter region and the 18 exons of the LDL - r gene were screened by touch - down polymerase chain reaction（PCR） and DNA sequencing. Results The caro- tid intima- media thickness（IMT） was increased to 0.23 cm, while coronary flow velocity reserve（CFVR） was decreased to 1.57, and mode- rate mitral regurgitation was found in the proband. The genetic alteration G→A change at 1 448 of exon 10 causing premature stop codon （W462X）. The same heterozygous nonsense mutation was also found in his father. The mutation had been reported in other Chinese patients. In vitro experiments showed that W462X mutation leads to low LDL binding and internalization ability. Conclusions The homozygous muta- tion（ W462X ） in exon 10 of the LDL- r gene were identified in the clinically heterozygous FH proband. The W462X mutation is the underlying cause of hypercholesterolaemia and clinical AS manifestations. W462X is recurrent mutation among Chinese FH patients. It might be a hot spot mutation in LDL- r in Chinese FH.