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目的探讨家族性高胆固醇血症(FH)患者低密度脂蛋白受体(LDL-R)基因突变与临床表型之间的关系。方法以FH先证者及其家系为研究对象,绘制家系图谱,对其成员进行常规体格检查、血脂测定、心电图、心血管超声等检查。以PCR法分别扩增启动子和全部18个外显子片段,产物经电泳鉴定后直接测序分析。同时PCR扩增ApoB100基因包含R3500Q,R3501W,R3531C和R3480W位点的序列,产物电泳鉴定后测序,以排除家族性载脂蛋白B100缺陷症(FDB)。结果共调查3代8人,先证者父母为姨表近亲结婚。家系中共有FH患者7例,7人血清总胆固醇均升高,临床诊断先证者为纯合子型,余均为杂合子型。系谱分析该家族遗传方式符合常染色体显性遗传规律。DNA测序排除该家系ApoB100基因R3500Q,R3501W,R3531C和R3480W位点突变,而先证者LDLR基因第2号外显子第97位编码碱基存在碱基置换(C→T),导致终止密码子在第12位提前出现,发生Q12X突变改变,基因型为TT纯合子;其父亲、母亲及胞弟均为携带Q12X突变的杂合子。结论先证者及其父母、胞弟LDL-R基因均存在Q12X突变,为终止突变,此位点的突变可能是该家系发病的分子基础。
Objective To investigate the relationship between low-density lipoprotein receptor (LDL-R) gene mutation and clinical phenotype in familial hypercholesterolemia (FH) patients. Methods FH probands and their families as the research object, drawn family map, the members of their regular physical examination, blood lipids, ECG, cardiovascular ultrasound and other tests. The promoter and all 18 exons were amplified by PCR respectively. The products were identified by electrophoresis and sequenced directly. At the same time, the ApoB100 gene was amplified by PCR and included the sequences of R3500Q, R3501W, R3531C and R3480W. The products were identified by electrophoresis and sequenced to eliminate familial apolipoprotein B100 deficiency (FDB). Results A total of 3 generations of 8 people surveyed, probationer parents aunt cousin married. Family FH patients in a total of 7 cases, 7 serum total cholesterol were elevated, the clinical diagnosis of proband as homozygous, I were more heterozygous. Pedigree analysis of the family’s genetic patterns consistent with autosomal dominant inheritance. DNA sequencing excised the ApoB100 gene R3500Q, R3501W, R3531C and R3480W locus mutations in the pedigree, whereas the 97th coding exon of LDLR gene in exon 2 showed a base substitution (C → T), leading to a stop codon in The first 12 occurred in advance, occurred Q12X mutation changes, genotype TT homozygotes; his father, mother and brother are Q12X mutation carrying heterozygotes. Conclusion The Q12X mutation exists in the probands, their parents and siblings, and is the termination mutation. The mutation in this locus may be the molecular basis of the disease.