Webb J C, Sun X M, McCarthy S N, Neuwirth C, Thompson G R, Knight B L, Soutar A K
MRC Lipoprotein Team, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
J Lipid Res. 1996 Feb;37(2):368-81.
Mutations in the gene for the low density lipoprotein (LDL) receptor have been identified in 15 patients with homozygous familial hypercholesterolemia (FH). Five patients are homozygous at the LDL-receptor locus; their mutant alleles include Glu387Lys and Pro664Leu in patients of Asian-Indian descent, Cys292Stop in a Greek Cypriot, Cys281Trp in a Turkish patient, and Gln 540Stop in a West Indian. The other 10 patients (9 of apparently British ancestry) are compound heterozygotes. Mutations have been identified in 18 of 20 possible alleles, including Glu80Lys (2 patients), Pro664Leu (3 patients), Asp69Gly, Cys176Arg, Cys227Tyr, Ser265Arg, Asp280Ala, Asp283Glu, Arg329Pro, Asp461Asn, Leu578Ser, a single bp deletion in exon 15, a 21 bp duplication of codons 200-206 and two large deletions. The seven mutations underlined above have not been described previously. The two uncharacterized mutant alleles fail to produce detectable amounts of mRNA. LDL-receptor activity in cultured cells from 13 of the 15 homozygous patients varied from undetectable to about 30% of normal, but there was no correlation between LDL-receptor activity and the untreated plasma cholesterol concentration in these patients. When genomic DNA from 295 patients with a clinical diagnosis of FH was screened for 29 mutations found in these and other FH patients of British ancestry, most were identified in only one or a few individuals. Four patients heterozygous for the Asp461Asn allele showed a wide range of clinical manifestations. These observations confirm the striking heterogeneity underlying FH in most populations and demonstrate the variability in phenotype between patients with the same mutation.
在15例纯合子家族性高胆固醇血症（FH）患者中已鉴定出低密度脂蛋白（LDL）受体基因的突变。5例患者在LDL受体位点为纯合子；他们的突变等位基因包括亚洲印度裔患者中的Glu387Lys和Pro664Leu、一名希腊塞浦路斯人中的Cys292Stop、一名土耳其患者中的Cys281Trp以及一名西印度人中的Gln 540Stop。另外10例患者（9例显然为英国血统）为复合杂合子。在20个可能的等位基因中的18个已鉴定出突变，包括Glu80Lys（2例患者）、Pro664Leu（3例患者）、Asp69Gly、Cys176Arg、Cys227Tyr、Ser265Arg、Asp280Ala、Asp283Glu、Arg329Pro、Asp461Asn、Leu578Ser、外显子15中的单个碱基缺失、密码子200 - 206的21个碱基重复以及两个大的缺失。上述下划线的7种突变以前未曾描述过。两个未鉴定特征的突变等位基因未能产生可检测量的mRNA。15例纯合子患者中13例患者培养细胞中的LDL受体活性从无法检测到正常水平的约30%不等，但这些患者的LDL受体活性与未经治疗的血浆胆固醇浓度之间无相关性。当对295例临床诊断为FH的患者的基因组DNA进行筛查，以寻找在这些及其他英国血统的FH患者中发现的29种突变时，大多数仅在一个或少数个体中被鉴定出。4例Asp461Asn等位基因杂合的患者表现出广泛的临床表现。这些观察结果证实了大多数人群中FH存在显著的异质性，并证明了相同突变患者之间表型的变异性。
