Bañares, V.G.; Corral, P.; Medeiros, A.M.; Araujo, M.B.; Lozada, A.; Bustamante, J.; Cerretini, R.; López, G.; Bourbon, M.; Schreier, L.E. "Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina" (2017) Journal of Clinical Lipidology. 11(2):524-531
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Background Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. Objective The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. Methods Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. Results Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics’ analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. Conclusion This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype–phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina. © 2017 National Lipid Association


Documento: Artículo
Título:Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina
Autor:Bañares, V.G.; Corral, P.; Medeiros, A.M.; Araujo, M.B.; Lozada, A.; Bustamante, J.; Cerretini, R.; López, G.; Bourbon, M.; Schreier, L.E.
Filiación:Departamento de Genética Experimental, Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud –ANLIS, “Dr Carlos Malbrán”, Ciudad Autónoma de Buenos Aires, Argentina
Departamento Investigación, Facultad de Medicina, Universidad FASTA, Buenos Aires, Argentina
Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal
Faculty of Sciences, University of Lisbon, BioISI – Biosystems & Integrative Sciences Institute, Lisboa, Portugal
Servicio de Nutrición, Hospital Nacional de Pediatría “Dr Juan P. Garraham”, Ciudad Autónoma de Buenos Aires, Argentina
Clínica de Lípidos, Universidad Austral, Buenos Aires, Argentina
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina
Facultad de Ingeniería, Universidad Nacional de Entre RíosEntre Ríos, Argentina
Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Universidad de Buenos Aires, Buenos Aires, Argentina
Universidad de Buenos Aires, Instituto de Fisiopatologia y Bioquímica Clinica, INFIBIOC, Buenos Aires, Argentina
Palabras clave:APOB; Argentina; Cardiovascular disease; Cardiovascular disease prevention; Cholesterol; Familial hypercholesterolemia; Genetic variants; LDLR gene; Mutations; Public health; asparagine; calcium ion; low density lipoprotein receptor; low density lipoprotein receptor; adolescent; adult; aged; Argentina; Article; bioinformatics; child; clinical article; exon; familial hypercholesterolemia; female; gene mutation; gene sequence; genetic analysis; genetic identification; genetic variability; heterozygote; homozygote; human; male; multiplex ligation dependent probe amplification; priority journal; sequence alignment; chemistry; familial hypercholesterolemia; genetic variation; genetics; metabolism; middle aged; molecular model; preschool child; protein conformation; young adult; Adolescent; Adult; Aged; Argentina; Child; Child, Preschool; Female; Genetic Variation; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Models, Molecular; Protein Conformation; Receptors, LDL; Young Adult
Página de inicio:524
Página de fin:531
Título revista:Journal of Clinical Lipidology
Título revista abreviado:J. Clin. Lipidology
CAS:asparagine, 70-47-3, 7006-34-0; calcium ion, 14127-61-8; Receptors, LDL


  • Nordestgaard, B.G., Chapman, M.J., Humphries, S.E., Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease (2013) Eur Heart J, 34 (45), pp. 3478-3490
  • Ademi, Z., Watts, G.F., Pang, J., Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia (2014) J Clin Lipidol, 8 (4), pp. 390-400
  • Watts, G.F., Gidding, S., Wierzbicki, A.S., Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation (2014) J Clin Lipidol, 8 (2), pp. 148-172
  • Pang, J., Lansberg, P.J., Watts, G.F., International developments in the care of familial hypercholesterolemia: where now and where to next? (2016) J Atheroscler Thromb, 23 (5), pp. 505-519
  • Hobbs, H.H., Brown, M.S., Goldstein, J.L., Molecular genetics of the LDL receptor gene in familial hypercholesterolemia (1992) Hum Mutat, 1 (6), pp. 445-466
  • Alberto, F.L., Figueiredo, M.S., Zago, M.A., Araújo, A.G., Dos-Santos, J.E., The Lebanese mutation as an important cause of familial hypercholesterolemia in Brazil (1999) Braz J Med Biol Res, 32 (6), pp. 739-745
  • Krisko, A., Etchebest, C., Theoretical model of human apolipoprotein B100 tertiary structure (2007) Proteins, 66 (2), pp. 342-358
  • Abifadel, M., Guerin, M., Benjannet, S., Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia (2012) Atherosclerosis, 223 (2), pp. 394-400
  • Caputo, M., Corach, D., Analysis of locus D9S1120 and its genetic admixture correlation in seven Argentina native American ethnic groups (2016) Am J Hum Biol, 28 (1), pp. 57-66
  • Vaca, G., Vàzquez, A., Magaña, M.T., Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia (2011) Atherosclerosis, 218 (2), pp. 391-396
  • Jannes, C.E., Santos, R.D., de Souza Silva, P.R., Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects (2015) Atherosclerosis, 238 (1), pp. 101-107
  • Miller, S.A., Dykes, D.D., Polesky, H.F., A simple salting out procedure for extracting DNA from human nucleated cells (1988) Nucleic Acids Res, 16 (3), p. 1215
  • Medeiros, A.M., Alves, A.C., Francisco, V., Bourbon, M., Update of the Portuguese familial hypercholesterolaemia study (2010) Atherosclerosis, 212 (2), pp. 553-558
  • Richards, S., Aziz, N., Bale, S., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (2015) Genet Med, 17 (5), pp. 405-423
  • Omasits, U., Ahrens, C.H., Müller, S., Wollscheid, B., Protter: interactive protein feature visualization and integration with experimental proteomic data (2014) Bioinformatics, 30 (6), pp. 884-886
  • Mata, N., Alonso, R., Badimón, L., Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART) (2011) Lipids Health Dis, 10, p. 94
  • Santos, R.D., Gidding, S.S., Hegele, R.A., Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel (2016) Lancet Diabetes Endocrinol, 4, pp. 850-861
  • Devoto, F.J., Argentine migration policy and movements of the European population (1876-1925) (1989) Estud Migr Latinoam, 4 (11), pp. 135-158
  • Dedoussis, G.V.Z., Pitsavos, C., Kelberman, D., FH-Pyrgos: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia (2003) Clin Genet, 64 (5), pp. 414-419
  • Li, H., Liu, J., Identification of heterogeneous nuclear ribonucleoprotein K as a transactivator for human low density lipoprotein receptor gene transcription (2010) J Biol Chem, 285 (23), pp. 17789-17797
  • De Castro-Orós, I., Pampín, S., Bolado-Carrancio, A., Functional analysis of LDLR promoter and 5′ UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia (2011) Hum Mutat, 32 (8), pp. 868-872
  • Chmara, M., Wasag, B., Zuk, M., Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations (2010) J Appl Genet, 51 (1), pp. 95-106
  • Leitersdorf, E., Tobin, E.J., Davignon, J., Hobbs, H.H., Common low-density lipoprotein receptor mutations in the French Canadian population (1990) J Clin Invest, 85 (4), pp. 1014-1023
  • Mozas, P., Castillo, S., Tejedor, D., Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR (2004) Hum Mutat, 24 (2), p. 187
  • Fouchier, S.W., Defesche, J.C., Umans-Eckenhausen, M.A., Kastelein, J.J., The molecular basis of familial hypercholesterolemia in the Netherlands (2001) Hum Genet, 109 (6), pp. 602-615
  • Damgaard, D., Jensen, H.K., Jensen, J.M., The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population (2005) Atherosclerosis, 180 (1), pp. 155-160
  • Cefalù, A.B., Barraco, G., Noto, D., Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent (2006) Int J Mol Med, 17 (3), pp. 539-546
  • Talmud, P.J., Shah, S., Whittall, R., Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study (2013) Lancet, 381 (9874), pp. 1293-1301
  • Alves, A.C., Benito-Vicente, A., Etxebarria, A., Medeiros, A.M., Martin, C., Genetic diagnosis of familial hypercholesterolaemia: the importance of an integrated analysis of clinical, molecular and functional data (2015) Atherosclerosis, 241 (1), pp. e111-e112. ,, Available at:
  • Santos, P.C.J.L., Morgan, A.C., Jannes, C.E., Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia (2014) Atherosclerosis, 233 (1), pp. 206-210
  • Palacios, L., Grandoso, L., Cuevas, N., Molecular characterization of familial hypercholesterolemia in Spain (2012) Atherosclerosis, 221 (1), pp. 137-142


---------- APA ----------
Bañares, V.G., Corral, P., Medeiros, A.M., Araujo, M.B., Lozada, A., Bustamante, J., Cerretini, R.,..., Schreier, L.E. (2017) . Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina. Journal of Clinical Lipidology, 11(2), 524-531.
---------- CHICAGO ----------
Bañares, V.G., Corral, P., Medeiros, A.M., Araujo, M.B., Lozada, A., Bustamante, J., et al. "Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina" . Journal of Clinical Lipidology 11, no. 2 (2017) : 524-531.
---------- MLA ----------
Bañares, V.G., Corral, P., Medeiros, A.M., Araujo, M.B., Lozada, A., Bustamante, J., et al. "Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina" . Journal of Clinical Lipidology, vol. 11, no. 2, 2017, pp. 524-531.
---------- VANCOUVER ----------
Bañares, V.G., Corral, P., Medeiros, A.M., Araujo, M.B., Lozada, A., Bustamante, J., et al. Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina. J. Clin. Lipidology. 2017;11(2):524-531.