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Received on November 8, 2004
Accepted on April 22, 2005
Molecular Diagnostics and Genetics |
1 Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
2 PROGENIKA BIOPHARMA S.A., Derio, Spain
3 Departamento de Anatomía, Embriología y Genética Animal, Universidad de Zaragoza, Zaragoza, Spain
4 Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Zaragoza, Spain
5 Unidad de Lípidos, Fundación Jiménez Díaz, Madrid, Spain
* To whom correspondence should be addressed. E-mail: dtejedor{at}progenika.com.
Background: Patients with familial hypercholesterolemia (FH) have a high risk of premature cardiovascular disease (PCVD). Mutations in the LDL receptor (LDLR) gene and the R3500Q mutation in the apolipoprotein B (APOB) gene are known to cause FH, but lack of high-throughput methods makes routine genetic diagnosis difficult. The objective of this work was to develop a DNA array for large-scale identification of mutant LDLR alleles.
Methods: We developed a low-density oligonucleotide microarray to identify 118 DNA sequence variations (117 for the LDLR gene and 1 for the APOB gene). We verified specificity and sensitivity by analyzing 1180 previously sequenced DNA samples, and conducted a blind study screening 407 Spanish patients with a clinical diagnosis of FH.
Results: The DNA array confirmed the previous genotyping results in almost all cases. In the blind study, the microarray detected at least 1 mutation in 51% of the patients for whom clinical diagnosis was classified as certain according to Dutch FH-MEDPED criteria; it also identified mutations in 37% of those with a diagnosis of probable/possible FH, thus giving a definite diagnosis. Patients harboring null mutations had shorter PCVD-free survival times and higher relative risk of PCVD than patients with a missense mutation.
Conclusions: The proposed DNA array allows large-scale population screening and provides molecular information regarding mutation type and its correlation with clinical severity of FH, which can be used to develop therapeutic strategies.
The following articles in journals at HighWire Press have cited this article:
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  K. P. Jeremy, Z. E. Plummer, D. J. Head, T. E. Madgett, K. L. Sanders, A. Wallington, J. R. Storry, F. Gilsanz, J. Delaunay, and N. D. Avent 4.1R-deficient human red blood cells have altered phosphatidylserine exposure pathways and are deficient in CD44 and CD47 glycoproteins Haematologica, October 1, 2009; 94(10): 1354 - 1361. [Abstract] [Full Text] [PDF]
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 S. E. Cabrera, D. Santos, M. P. Valverde, A. Dominguez-Gil, F. Gonzalez, G. Luna, and M. J. Garcia Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients Antimicrob. Agents Chemother., July 1, 2009; 53(7): 2791 - 2798. [Abstract] [Full Text] [PDF]
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 F. Civeira, E. Jarauta, A. Cenarro, A. L. Garcia-Otin, D. Tejedor, D. Zambon, M. Mallen, E. Ros, and M. Pocovi Frequency of Low-Density Lipoprotein Receptor Gene Mutations in Patients With a Clinical Diagnosis of Familial Combined Hyperlipidemia in a Clinical Setting J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1546 - 1553. [Abstract] [Full Text] [PDF]
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G. P. Jarvik, J. D. Brunzell, and A. G. Motulsky Frequent Detection of Familial Hypercholesterolemia Mutations in Familial Combined Hyperlipidemia J. Am. Coll. Cardiol., November 4, 2008; 52(19): 1554 - 1556. [Full Text] [PDF]
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 D. Tejedor, S. Castillo, P. Mozas, E. Jimenez, M. Lopez, M. T. Tejedor, M. Artieda, R. Alonso, P. Mata, L. Simon, et al. Comparison of DNA Array Platform vs DNA Sequencing as Genetic Diagnosis Tools for Familial Hypercholesterolemia. Clin. Chem., October 1, 2006; 52(10): 1971 - 1972. [Full Text] [PDF]
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S. Blesa, A. B. Garcia-Garcia, S. Martinez-Hervas, M. L. Mansego, V. Gonzalez-Albert, J. F. Ascaso, R. Carmena, J. T. Real, and F. J. Chaves Analysis of Sequence Variations in the LDL Receptor Gene in Spain: General Gene Screening or Search for Specific Alterations? Clin. Chem., June 1, 2006; 52(6): 1021 - 1025. [Abstract] [Full Text] [PDF]
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 M. Junyent, M. Cofan, I. Nunez, R. Gilabert, D. Zambon, and E. Ros Influence of HDL Cholesterol on Preclinical Carotid Atherosclerosis in Familial Hypercholesterolemia Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1107 - 1113. [Abstract] [Full Text] [PDF]
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F. Civeira, S. Castillo, R. Alonso, E. Merino-Ibarra, A. Cenarro, M. Artied, P. Martin-Fuentes, E. Ros, M. Pocovi, P. Mata, et al. Tendon Xanthomas in Familial Hypercholesterolemia Are Associated With Cardiovascular Risk Independently of the Low-Density Lipoprotein Receptor Gene Mutation Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1960 - 1965. [Abstract] [Full Text] [PDF]
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