cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLCcardiovascular-1395Research ArticleДИСЛИПИДЕМИИСемейный дефект аполипопротеина В-100: молекулярная основа заболевания и клинико-биохимические особенности пациентовFamilial defect of apolipoprotein В-100: molecular disease basis and clinico-biochemical characteristics of the patientsМалышевП. П.MalyshevP. P.ppmal@rambler.ruМешковА. Н.MeshkovA. N.ppmal@rambler.ruКотоваЛ. А.KotovaL. A.ppmal@rambler.ruКухарчукВ. В.KukharchukV. V.ppmal@rambler.ruИнститут клинической кардиологии им. А.Л.Мясникова РКНПК Росздрава, МоскваA.L. Myasnikov Research Institute of Clinical Cardiology, Russian Cardiology Scientific and Clinical Complex, Russian Federal Agency for Health and Social Development, Moscow200720122007664045Copyright © Малышев П.П., Мешков А.Н., Котова Л.А., Кухарчук В.В., 20072007Малышев П.П., Мешков А.Н., Котова Л.А., Кухарчук В.В.Malyshev P.P., Meshkov A.N., Kotova L.A., Kukharchuk V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/1395

Цель. Определить характер и частоту мутаций гена аполипопротеина (апо) В-100 у пациентов с клиническим диагнозом гетерозиготной семейной гиперхолестеринемии (СГ) и охарактеризовать фенотипические проявления у носителей мутации. Материал и методы. Скрининг на мутации в 26-м экзоне гена апо В-100 был проведен среди 111 пациентов с клиническим диагнозом гетерозиготной СГ. При анализе дезоксирибонуклеиновой кислоты (ДНК) использовали аллельспецифическую полимеразную цепную реакцию, рестрикционный анализ, анализ полиморфизма конформации одноцепочечного фрагмента ДНК (SSCP) и секвенирование участков ДНК с аномальной электрофоретической подвижностью. Результаты. Среди больных с клиническими проявлениями гетерозиготной СГ у 4,5% была обнаружена мутация гена апо В-100. Мутация R3500Q была единственным видом нарушения в структуре гена апо В-100 у обследованных пациентов. Больные с дефектом апо В-100 по сравнению с носителями мутации рецептора липопротеина низкой плотности (ЛНП-рецептора) характеризовались менее выраженной ГХС. Заключение. Мутация R3500Q гена апо В-100 наряду с мутациями ЛНП-рецептора является одной из причин высокого уровня ХС у российских пациентов, в то время как другие мутации 26-го экзона гена этого белка, по-видимому, очень редки.

Aim. To identify character and prevalence of apolipoprotein (apo) B-100 gene mutation in patients with clinical diagnosis of heterozygote familial hypercholesterolemia (FH); to describe its phenotypical features in mutation carriers. Material and methods. In 111 patients with clinical diagnosis of heterozygote FH, screening for exon 26 apo B-100 gene mutations was performed. For DNA analysis, allele-specific PCR, restriction analysis, analysis of DNA single-strand conformation polymorphism (SSCP), and sequestering of DNA fragments with anomaly electrophoretic activity were used. Results. In patients with clinics of heterozygote FH, 4,5% had apo B-100 gene mutation. R3500Q mutation was the only apo B-100 gene structure anomaly observed in these individuals. Compared to patients with low-density lipoprotein (LDL) receptor mutation, subjects with apo B-100 defect had less manifested HCH. Conclusion. R3500Q mutation of apo B-100 gene, together with LDL receptor mutations, partially explain high CH levels in Russian patients. Other mutations of this protein’s exon 26 could be very rare.

семейный дефект апо В-100гиперхолестеринемияксантомыfamilial apo B-100 defecthypercholesterolemiaxanthomasReferencesVega GL, Grundy SM. In vivo evidence for reduction binding of low density lipoprotein to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 1986; 78: 1410-8.Vega GL, Grundy SM. In vivo evidence for reduction binding of low density lipoprotein to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 1986; 78: 1410-8.Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84: 6919- 23.Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84: 6919- 23.Soria LF, Ludwig EH, Clarke HRG, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989; 86: 587-91.Soria LF, Ludwig EH, Clarke HRG, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989; 86: 587-91.Myant NB. Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 1993; 104: 1-18.Myant NB. Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 1993; 104: 1-18.Rauh G, Keller C, Schuster H, et al. Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia. J Clin Invest 1992; 70: 77-84.Rauh G, Keller C, Schuster H, et al. Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia. J Clin Invest 1992; 70: 77-84.Fisher E, Scharnagl H, Hoffmann MM, et al. Mutations in the apolipoprotein (apo) B-100 receptor binding region: detection of apo B-100 (Arg35006Trp) associated with two new haplotypes and evidence that apo B-100 (Glu34056Gln) diminishes receptor-mediated uptake of LDL. Clin Chem 1999; 45: 1026-38.Fisher E, Scharnagl H, Hoffmann MM, et al. Mutations in the apolipoprotein (apo) B-100 receptor binding region: detection of apo B-100 (Arg35006Trp) associated with two new haplotypes and evidence that apo B-100 (Glu34056Gln) diminishes receptor-mediated uptake of LDL. Clin Chem 1999; 45: 1026-38.Hansen PS. Familial defective apolipoprotein B-100. Dan Med Bull 1998; 45: 370-82.Hansen PS. Familial defective apolipoprotein B-100. Dan Med Bull 1998; 45: 370-82.Gaffney D, Reid JM, Cameron IM, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidaemia. Arterioscler Thromb Vasc Biol 1995; 15: 1025-9.Gaffney D, Reid JM, Cameron IM, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidaemia. Arterioscler Thromb Vasc Biol 1995; 15: 1025-9.Pullinger CR, Hennessy LK, Chatterton JE, et al. Familial ligand-defective apolipoprotein B: identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest 1995; 95: 1225-34.Pullinger CR, Hennessy LK, Chatterton JE, et al. Familial ligand-defective apolipoprotein B: identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest 1995; 95: 1225-34.Boren J, Ekstrom U, Agren B, et al. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem 2001; 276: 9214-8.Boren J, Ekstrom U, Agren B, et al. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem 2001; 276: 9214-8.Pogoda T, Metelskaya V, Perova N, et al. Detection of apoB-3500 mutation in a Russian family with coronary heart disease. Hum Hered 1998; 48: 291-2.Pogoda T, Metelskaya V, Perova N, et al. Detection of apoB-3500 mutation in a Russian family with coronary heart disease. Hum Hered 1998; 48: 291-2.WHO-Human Genetics, DoNDP, Familial Hypercholesterolaemia – Report of a second WHO Consultation, ed. WHO. 1999, GenevaWHO-Human Genetics, DoNDP, Familial Hypercholesterolaemia – Report of a second WHO Consultation, ed. WHO. 1999, GenevaМешков А.Н., Стамбольский Д.В., Крапивнер C.Р. и др. Мутации гена рецептора липопротеинов низкой плотности у пациентов с клиническим диагнозом семейной гиперхолестеринемии. Кардиология 2004; 9: 58-61.Мешков А.Н., Стамбольский Д.В., Крапивнер C.Р. и др. Мутации гена рецептора липопротеинов низкой плотности у пациентов с клиническим диагнозом семейной гиперхолестеринемии. Кардиология 2004; 9: 58-61.Boren J, Lee I, Zhu W, et al. Identification of the low-density lipoprotein receptor-binding site in apolipoprotein B100 and modulation of its binding activity by the carboxyl terminus in familial defective apo B-100. J Clin Invest 1998; 101: 1084-93.Boren J, Lee I, Zhu W, et al. Identification of the low-density lipoprotein receptor-binding site in apolipoprotein B100 and modulation of its binding activity by the carboxyl terminus in familial defective apo B-100. J Clin Invest 1998; 101: 1084-93.Miserez AR, Muller PY. Familial defective apolipoprotein B-100: a mutation emerged in the Mesolithic ancestors of Celtic peoples? Atherosclerosis 2000; 148: 433-6.Miserez AR, Muller PY. Familial defective apolipoprotein B-100: a mutation emerged in the Mesolithic ancestors of Celtic peoples? Atherosclerosis 2000; 148: 433-6.Kalina A, Csaszar A, Czeizel A, et al. Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary. Atherosclerosis 2001; 154: 247-51.Kalina A, Csaszar A, Czeizel A, et al. Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary. Atherosclerosis 2001; 154: 247-51.Schwartz EI, Shevtsov SP, Kuchinski AP, et al. Approach to identification of point mutation in apolipoprotein B-100 gene by means of PCR-mediated site-directed mutagenesis. Nucleic Acids Res 1991; 19: 3752.Schwartz EI, Shevtsov SP, Kuchinski AP, et al. Approach to identification of point mutation in apolipoprotein B-100 gene by means of PCR-mediated site-directed mutagenesis. Nucleic Acids Res 1991; 19: 3752.Шевцов С.П. Отсутствие ДНК-полиморфизмов на участке гена APOB, кодирующем предполагаемый домен связывания белка ApoB-100 с рецептором липопротеидов низкой плотности. Генетика 1996; 2: 295-7.Шевцов С.П. Отсутствие ДНК-полиморфизмов на участке гена APOB, кодирующем предполагаемый домен связывания белка ApoB-100 с рецептором липопротеидов низкой плотности. Генетика 1996; 2: 295-7.Zakharova FM, Damgaard D, Mandelshtam MY, et al. Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med Genet 2005; 6: 6.Zakharova FM, Damgaard D, Mandelshtam MY, et al. Familial hypercholesterolemia in St.-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med Genet 2005; 6: 6.Defesche JC, Pricker LK, Hayden RM, et al. Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med 1993; 153: 2349-56.Defesche JC, Pricker LK, Hayden RM, et al. Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med 1993; 153: 2349-56.Talmud P, Tamplin JO, Heath K, et al. Rapid testing for three mutations causing familial defective apolipoprotein B100 in 562 patients with familial hypercholesterolaemia. Atherosclerosis 1996; 125: 135-7.Talmud P, Tamplin JO, Heath K, et al. Rapid testing for three mutations causing familial defective apolipoprotein B100 in 562 patients with familial hypercholesterolaemia. Atherosclerosis 1996; 125: 135-7.Miserez AR, Keller N. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 1719-29.Miserez AR, Keller N. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 1719-29.Brousseau T, Arveiler D, Cambou JP, et al. Familial defective apolipoprotein B-100 and myocardial infarction. The ECTIM study. Atherosclerosis 1995; 116: 267-71.Brousseau T, Arveiler D, Cambou JP, et al. Familial defective apolipoprotein B-100 and myocardial infarction. The ECTIM study. Atherosclerosis 1995; 116: 267-71.Tybjaerg-Hansen A, Humphries SE. Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 1992; 96: 91-107.Tybjaerg-Hansen A, Humphries SE. Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 1992; 96: 91-107.Tybjaerg-Hansen A, Steffensen R, Meinertz H, et al. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 1998; 338: 1548-77.Tybjaerg-Hansen A, Steffensen R, Meinertz H, et al. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 1998; 338: 1548-77.Vrablik M, Ceska R, Horinek A. Major apolipoprotein B-100 mutations in lipoprotein metabolism and atherosclerosis. Physiol Res 2001; 50: 337-43.Vrablik M, Ceska R, Horinek A. Major apolipoprotein B-100 mutations in lipoprotein metabolism and atherosclerosis. Physiol Res 2001; 50: 337-43.Soufi M, Sattler AM, Maerz W, et al. A new but frequent muta- tion of apoB-100 - apoB His3543Tyr. Atherosclerosis 2004; 174: 11-6.Soufi M, Sattler AM, Maerz W, et al. A new but frequent muta- tion of apoB-100 - apoB His3543Tyr. Atherosclerosis 2004; 174: 11-6.

The authors declare that there are no conflicts of interest present.