Información del artículo
Fundamento
La hiperlipoproteinemia tipo III (HLP tipo III) se caracteriza por el catabolismo reducido y la acumulación de lipoproteínas remanentes. La mayoría de pacientes con HLP tipo III son homocigotos para el alelo de la apolipoproteína (apo) є2 (Cys112, Cys158). Sin embargo, se han descrito otras variantes de apo E que, en heterocigosidad, están asociadas con HLP tipo III. Recientemente hemos identificado una de estas variantes, apo E 2 Arg136Ser.
MétodosCon objeto de analizar su prevalencia y de profundizar en el conocimiento de las características hereditarias de la HLP tipo III asociada a esta variante, hemos determinado, utilizando la reacción en cadena de la polimerasa (PCR) y análisis de restricción, los genotipos de apo Å en 230 pacientes con hiperlipemia mixta y en 1.202 muestras de ADN de sujetos procedentes de la Comunidad Autónoma de Aragón: 103 recién nacidos y 1.109 sujetos de edades comprendidas entre 2 y 92 años.
ResultadosLa frecuencia estimada del alelo apo є2 Arg136Ser fue de 0,0037. Hemos identificado a un total de 43 sujetos portadores de esta variante, 17 de los cuales (39%) tenían HLP tipo III. La mutación se asocia con dominancia parcial de HLP tipo III, y la expresión de la hiperlipemia en los sujetos portadores depende, entre otros factores, de la edad, índice de masa corporal y sexo.
ConclusiónLa variante apo E 2 Arg136Ser es aparentemente frecuente en nuestra población y está asociada con HLP tipo III y dominancia incompleta.
Palabras clave:
Apolipoproteína E
Hiperlipoproteinemia
Lipoproteínas
Genética
Background
Type III hyperlipoproteinemia (type III HLP) is characterized by reduced catabolism and accumulation of remnant lipoprotein particles. Most type III HLP patients are homozygous for the apolipoprotein (apo) є2 (Cys112, Cys158) allele. However, several other rare variants at this locus have been associated in heterozygous state with type III HLP. Recently, one of these variants, apo E 2 Arg136Ser has been identified in Spanish population and reported to be associated with type III HLP.
MethodsIn order to assess the prevalence of this rare variant in our population and the inheritance characteristics of type III HLP linked to this apo E variant, we have examined the apo Å genotype by restriction enzyme analysis of polymerase chain reaction (PCR) product in 230 patients with mixed hyperlipidemia and 1,202 subjects from the Comunidad Autónoma de Aragón (Spain): 103 unrelated newborns and 1,109 subjects (2-92 years old).
ResultsThe estimated apo є2 Arg136Ser allele frequency in this population was 0.0037. We have identified 43 carriers of the apo є2 Arg136Ser allele, and 39% of them disclose type III HLP. This mutation is associated with partial dominance of type III HLP and expression of hyperlipidemia in carriers shows different penetration depending on age, body mass index and gender.
ConclusionThe apo E 2 Arg136Ser variant might be frequent in our population and it is associated with incomplete dominance of type III HLP.
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Bibliografía
[1.]
R.J. Havel, Y.C. Chao, E.E. Windler, L. Kotite, L.S.S. Guo.
Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia.
Proc Natl Acad Sci USA, 77 (1980), pp. 4339-4353
[2.]
B.C. Sherril, T.L. Innerarity, R.W. Mahley.
Rapid hepatic clearance of the canine lipoprotein containing only the E apolipoprotein by high affinity receptor.
J Biol Chem, 225 (1980), pp. 1804-1807
[3.]
P. Barter.
High density lipoproteins and reverse cholesterol transport.
Curr Opin Lipidol, 4 (1993), pp. 210-214
[4.]
C. Wilson, M.R. Wardell, K.H. Weisgraber, R.W. Mahley, D.A. Agard.
Three-dimensional structure of the receptor binding domain of human apolipoprotein E.
Science, 252 (1991), pp. 1817-1822
[5.]
K.H. Weisgraber, S.C. Rall, R.W. Mahley.
Human apoprotein E heterogeneity: cysteine-arginine interchanges in the aminoacid sequence of the apoE isoforms.
J Biol Chem, 256 (1981), pp. 9077-9083
[6.]
C.F. Sing, J. Davignon.
Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.
Am J Hum Genet, 37 (1985), pp. 268-285
[7.]
R.W. Mahley, S.C. Rall.
Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.
The metabolic and molecular basis of inherited diseases (7.a ed.), pp. 1953-1980
[8.]
M.K. Polano.
Xanthoma types in relation to the type of hyperlipoproteinemia.
Nutr Metab, 15 (1973), pp. 107-118
[9.]
G. Utermann.
Morgani Lecture. Genetic polymorphism of apolipoprotein E. Impact on plasma lipoprotein metabolism.
Diabetes, obesity and hyperlipidemia, pp. 1-28
[10.]
R.W. Mahley, T.L. Innerarity, S.C. Rall Jr., K.H. Weisgraber, J.M. Taylor, E. Apolipoprotein.
Genetic variants provide insight into its structure and function.
Curr Opin Lipidol, 1 (1990), pp. 87-95
[11.]
S.C. Rall Jr., T.L. Innerarity, K.H. Weisgraber, M.R. Wardell, R.W. Mahley.
The type of mutation in apolipoprotein E determines whether type III hyperlipoproteinemia is expressed as a dominant or recesive trait.
Proceeding of the seventh atherosclerosis and cardiovascular disease conference, pp. 81-88
[12.]
M. Pocoví, A. Cenarro, F. Civeira, R.H. Myers, E. Casao, M. Esteban, et al.
Incomplete dominance of type III hyperlipoproteinemia associated with the rare apolipoprotein E2 (Arg136 ??Ser) variant in multigenerational pedigree studies.
Atherosclerosis, 122 (1996), pp. 33-46
[13.]
F. Civeira, M. Pocoví, A. Cenarro, E. Casao, E. Villella, J. Joven, et al.
Apo E variants in patients with type III hyperlipidemia.
Atherosclerosis, 127 (1996), pp. 273-282
[14.]
F. Civeira, M. Pocoví, A. Moreda, J. Alamillo, P. Cía, F. Grande.
Niveles de colesterol y triglicéridos, y distribución del colesterol en lipoproteínas en una población laboral. Varones.
Clin Invest Arteriosclerosis, 2 (1990), pp. 43-47
[15.]
A. Moreda, J. Alamillo, M. Pocoví, F. Civeira, M. Blasco, J.M. Ordovás.
Niveles de colesterol y triglicéridos, y distribución del colesterol en lipoproteínas en una población laboral. Mujeres.
Clin Invest Arterioscler, 2 (1990), pp. 48-54
[16.]
R.J. Havel, H.A. Eder, J.H. Bragdom.
Distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
J Clin Invest, 34 (1955), pp. 1345-1355
[17.]
S. Miller, D. Dykes, H. Polensky.
A simple salting out procedure for extracting DNA from human nucleated cells.
Nucleic Acids Res, 16 (1988), pp. 1215
[18.]
S. Castillo, A. Cenarro, F. Civeira, A. Gañán, A.L. García Otín, C. Gonzalvo, et al.
Técnicas especiales para el diagnóstico de las alteraciones del metabolismo lipídico.
Clin Invest Arterioscler, 11 (1999), pp. 205-224
[19.]
R.W. Mahley, Z.S. Ji.
Remnant lipoprotein metabolism key pathways involving cell-surface heparan proteoglycans and apolipoprotein E.
J Lipid Res, 40 (1999), pp. 1-16
[20.]
E. De Faria, L.G. Fong, M. Komaromy, A.D. Cooper.
Relative roles of the LDL receptor, the LDL receptor-like protein and hepatic lipase in chylomicron remnant removal by the liver.
J Lipid Res, 37 (1996), pp. 197-208
[21.]
W.A. Mann, P. Lohse, R.E. Gregg, R. Ronan, J.M. Hoeg, L.A. Zech, et al.
Dominant expression of type III Hyperlipoproteinemia. Pathological insights derived from structural and kinetics characteristics of Apo E-1 (Lys146 ??Glu.
J Clin Invest, 96 (1995), pp. 1100-1107
[22.]
S. Tajima, T. Yamamura, A. Yamamoto.
Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia.
J Biochem (Tokyo, 104 (1988), pp. 48-52
[23.]
F. Mailly, C.F. Xu, M. Xhignesse, S. Lussier-Cacan, P.J. Talmud, J. Davignon, et al.
Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects.
J Lipid Res, 32 (1991), pp. 613-620
[24.]
P. Lohse, W.A. Mann, E.A. Stein, H.B. Brewer.
Apolipoprotein E 4 Philadelphia (Glu13?Lys, Arg 145?Cys). Homozigosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia.
J Biol Chem, 266 (1991), pp. 10479-10484
[25.]
G. Feussner, V. Feussner, M.M. Hoffman, J. Lohrmann, H. Wieland, W. Marz.
Molecular basis of type III hyperlipoproteinemia in Germany.
Hum Mutat, 11 (1998), pp. 417-423
[26.]
A. Matsunaga, J. Sasaki, T. Komatsu, K. Kanatsu, E. Tsuji, K. Moriyama, et al.
A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy.
Kidney Int, 56 (1999), pp. 421-427
[27.]
M. Orth, W. Weng, H. Funke, A. Steinmetz, G. Assmann, M. Nauck, et al.
Effects of a frequent apolipoprotein E isoform, ApoE4 Freiburg (Leu28?Pro), on lipoproteins and the prevalence of coronary artery disease in whites.
Arterioscler Thromb Vasc Biol, 19 (1999), pp. 1306-1315
[28.]
G. Feussner, H. Funke, W. Weng, G. Assmann, K.J. Lackner, R. Ziegler.
Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’ genotype.
Eur J Clin Invest, 22 (1992), pp. 599-608
[29.]
H. Wieland, H. Funke, J. Krieg, C. Luley.
Apo E3Freiburg and apo E4Freiburg are two genetic apo E variants which are caused by exchanges of uncharged aminoacids and do not appear to be associated with lipid disorders or heart disease.
Abstract Book of the Ninth International Symposium on Atherosclerosis, Rosemont, Illinois, EE.UU, (1991), pp. 164
[30.]
V. Ruzicka, W. Marz, A. Russ, E. Fisher, W. Mondorf, W. Gross.
Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81?Lys, Cys112?Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis.
Electrophoresis, 14 (1993), pp. 1032-1037
[31.]
M.R. Wardell, S.C. Rall, E.J. Schaefer, J.P. Kane, K.H. Weisgraber.
Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity.
J Lipid Res, 32 (1991), pp. 521-528
[32.]
J.W. McLean, N.A. Elshourbagy, D.J. Chang, R.W. Mahley, J.M. Taylor.
Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant.
J Biol Chem, 259 (1984), pp. 6498-6504
[33.]
M.R. Wardell, K.H. Weisgraber, L.M. Havekes, S.C. Rall.
Apolipoprotein E3-Leiden contains a seven-aminoacid insertion that is a tandem repeat of residues 121-127.
J Biol Chem, 264 (1989), pp. 21205-21210
[34.]
K.H. Weisgraber, S.C. Rall, T.L. Innerarity, R.W. Mahley, T. Kuusi, C. Ehnholm.
A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1.
J Clin Invest, 73 (1984), pp. 1024-1033
[35.]
P. De Knijff, A.M. van den Maagdenberg, R.R. Frants, L.M. Havekes.
Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.
Hum Mutat, 4 (1994), pp. 178-194
[36.]
A. Minnich, K.H. Weisgraber, Y. Newhouse, L.M. Dong, L.J. Fortin, M. Tremblay, et al.
Identification of a novel apolipoprotein E variant, apolipoprotein E3’ (Arg136?His): association with mild dyslipidemia and double pre-beta very low density lipoproteins.
J Lipid Res, 36 (1995), pp. 57-66
[37.]
M.R. Wardell, S.O. Brennan, E.D. Janus, R. Fraser, R.W. Carrell.
Apolipoprotein E2-Christchurch (Arg136?Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia.
J Clin Invest, 80 (1987), pp. 483-490
[38.]
C.C. Walden, M.W. Huff, L.A. Leiter, P.W. Connelly, R.A. Hegele.
Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping.
J Clin Endocrinol Metab, 78 (1994), pp. 699-704
[39.]
K. Konishi, T. Saruta, S. Kuramochi, S. Oikawa, T. Saito, H. Han, et al.
Association of a novel 3-aminoacid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy.
Nephron, 83 (1999), pp. 214-218
[40.]
H. Hattori, M. Nagano, T. Egashira, T. Ogawa, H. Arai, T. Watanabe, et al.
A novel mutation of the apolipoprotein E gene in a patient with lipoprotein glomerulopathy.
Atherosclerosis, 144 (Supl 1 (1999), pp. 104
[41.]
P. Richard, M.P. De Zulueta, I. Beucler, J.L. De Gennes, A. Cassaigne, A. Iron.
Identification of a new apolipoprotein E variant (E2 Arg142 ??Leu) in type III hyperlipidemia.
Atherosclerosis, 112 (1995), pp. 19-28
[42.]
Y. Horie, S. Fazio, J.R. Westerlund, K.H. Weisgraber, S.C. Rall.
The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia.
J Biol Chem, 267 (1992), pp. 1962-1968
[43.]
W.J. De Villiers, D.R. Van der Westhuyzen, G.A. Coetzee, H. Henderson, A.D. Marais.
The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance.
Arterioscler Thromb Vasc Biol, 17 (1997), pp. 865-872
[44.]
S. Oikawa, A. Matsunaga, T. Saito, H. Sato, T. Seki, K. Hoshi, et al.
Apolipoprotein E Sendai (arginine 145 ??proline): a new variant associated with lipoprotein glomerulopathy.
J Am Soc Nephrol, 8 (1997), pp. 820-823
[45.]
T. Suehiro, K. Yoshida, T. Yamano, F. Ohno.
Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi.
Jpn J Med, 29 (1990), pp. 587-594
[46.]
W.A. Mann, R.E. Gregg, D.L. Sprecher, H.B. Brewer.
Apolipoprotein E- 1 Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia.
Biochim Biophys Acta, 1005 (1989), pp. 239-244
[47.]
S.C. Rall, K.H. Weisgraber, T.L. Innerarity, T.P. Bersot, R.W. Mahley, C.B. Blum.
Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype.
J Clin Invest, 72 (1983), pp. 1288-1297
[48.]
M.J. Hoffer, S. Nithyananthan, R.P. Naumova, M.S. Kibrige, R.R. Frants, L.M. Havekes, et al.
Apolipoprotein E1-Hammersmith (Lys146 ??Asn; Arg147 ??Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinemia.
Atherosclerosis, 124 (1996), pp. 183-189
[49.]
K.J. Livak, J.W. Hainer.
A microtiter plate assay for determining apolipoprotein E genotype and discovery of a rare allele.
Hum Mutat, 3 (1994), pp. 379-385
[50.]
M. Ando, J. Sasaki, H. Hua, A. Matsunaga, K. Uchida, K. Jou, et al.
A novel 18-aminoacid deletion in apolipoprotein E associated with lipoprotein glomerulopathy.
Kidney Int, 56 (1999), pp. 1317-1323
[51.]
M. Okubo, Y. Aoyama, K. Harada, M. Fukawa, T. Tsukada, H. Mokuno, et al.
A novel apolipoprotein E2 variant, E2 Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis.
Atherosclerosis, 140 (1998), pp. 187-190
[52.]
G. Feussner, J. Dobmeyer, H.J. Grone, S. Lohmer, S. Wohlfeil.
A 10- bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia.
Am J Hum Genet, 58 (1996), pp. 281-291
[53.]
P. Lohse, H.B. Brewer, M.S. Meng, S.I. Skarlatos, J.C. LaRosa, H.B. Brewer Jr..
Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene.
J Lipid Res, 33 (1992), pp. 1583-1590
[54.]
G. Feussner, H. Scharnagl, C. Scherbaum, J. Acar, J. Dobmeyer, J. Lohrmann, et al.
Apolipoprotein E5 (Glu212 ??Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts.
J Lipid Res, 37 (1996), pp. 1632-1645
[55.]
K. Moriyama, J. Sasaki, Y. Takada, F. Arakawa, A. Matsunaga, Y. Ito, et al.
Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224?Gln) in a hyperlipidemic patient with xanthomatosis.
Biochim Biophys Acta, 1301 (1996), pp. 185-190
[56.]
M.R. Wardell, S.C. Rall, S.O. Brennan, E.R. Nye, P.M. George, E.D. Janus, et al.
Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity.
J Lipid Res, 31 (1990), pp. 535-543
[57.]
A.M. Van den Maagdenbergs, W. Weng, I.H. De Bruijn, P. De Knijff, H. Funke, A.H. Smelt, et al.
Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia.
Am J Hum Genet, 52 (1993), pp. 937-946
[58.]
T. Yamamura, L.M. Dong, A. Yamamoto.
Characterization of apolipoprotein E7 (Glu244’Lys, Glu245’Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis.
J Lipid Res, 40 (1999), pp. 253-259
[59.]
G. Ghiselli, R.E. Gregg, H.B. Brewer.
Apolipoprotein E Bethesda. Isolation and partial characterization of a variant of human apolipoprotein E isolated from very low density lipoproteins.
Biochim Biophys Acta, 794 (1984), pp. 333-339
[60.]
C. Cladaras, M. Hadzopoulou-Cladaras, B.K. Felber, G. Pavlakis, V.I. Zannis.
The molecular basis of a familial apo E deficiency. An acceptor splice site mutation in the third intron of the deficient apo E gene.
J Biol Chem, 262 (1987), pp. 2310-2315
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