Abstract
Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.
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Acknowledgements
We thank the family members for their cooperation. This work was supported by grants from Pfizer, Fondation de France, GIS-Maladies Rares, PHRC (AOM06024), and ANR (ANR-05-PCOD-017, ANR-06-MRAR-038, ANR-08-GENO-002-01). AM-P and MM are supported by a grant from the Ministère de l’Education Nationale et de la Technologie (France). MA is supported by grants from Région Ile de France and Conseil de la Recherche de l’Université Saint-Joseph (Beirut, Lebanon).
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Marques-Pinheiro, A., Marduel, M., Rabès, JP. et al. A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1. Eur J Hum Genet 18, 1236–1242 (2010). https://doi.org/10.1038/ejhg.2010.94
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DOI: https://doi.org/10.1038/ejhg.2010.94
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