Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations

被引:55
作者
Chmara, M. [1 ]
Wasag, B. [1 ]
Zuk, M. [1 ]
Kubalska, J. [2 ,3 ]
Wegrzyn, A. [4 ]
Bednarska-Makaruk, M. [3 ]
Pronicka, E. [2 ]
Wehr, H. [3 ]
Defesche, J. C. [5 ]
Rynkiewicz, A. [4 ]
Limon, J. [1 ]
机构
[1] Med Univ Gdansk, Dept Biol & Genet, PL-80210 Gdansk, Poland
[2] Childrens Mem Hlth Inst, Dept Metab Dis Endocrinol & Diabetol, Warsaw, Poland
[3] Inst Psychiat & Neurol, Dept Genet, Warsaw, Poland
[4] Med Univ Gdansk, Dept Cardiol 1, PL-80210 Gdansk, Poland
[5] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands
关键词
APOB; apolipoprotein B-100; familial hypercholesterolemia; LDLR; low-density lipoprotein receptor; mutations; DEFECTIVE APOLIPOPROTEIN B-100; B GENE; IDENTIFICATION; B100; CHOLESTEROL; NETHERLANDS; CODON-3500; FREQUENCY; DIAGNOSIS; REGION;
D O I
10.1007/BF03195716
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and a fragment of exon 26 of APOB. Additionally, the MLPA technique was applied to detect rearrangements within LDLR. In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR, 40 novel and 59 previously described Sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4-8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB. Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the Studied group confirms the requirement for complex molecular Studies of Polish ADH patients.
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页码:95 / 106
页数:12
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