1. New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia
- Author
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Jean-Pierre Rabès, Mathilde Varret, Catherine Boileau, Marianne Abifadel, Eric Bruckert, Gina M. Peloso, Ali Ben-Djoudi-Ouadda, Josée Hamelin, Nabil G. Seidah, Youmna Ghaleb, Nathan O. Stitziel, Valérie Carreau, Petra El Khoury, Sandy Elbitar, Delia Susan-Resiga, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Saint-Joseph de Beyrouth (USJ), Université Paris Diderot - Paris 7 (UPD7), Université de Montréal (UdeM), Boston University [Boston] (BU), The McDonnell Genome Institute (MGI), Washington University in Saint Louis (WUSTL), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
- Subjects
0301 basic medicine ,Male ,Heterozygote ,Apolipoprotein B ,lcsh:Medicine ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Compound heterozygosity ,Article ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Chromosome Segregation ,medicine ,Humans ,Family ,lcsh:Science ,Gene ,Exome ,Exome sequencing ,Apolipoproteins B ,Genetics ,Mutation ,Multidisciplinary ,biology ,lcsh:R ,nutritional and metabolic diseases ,High-Throughput Nucleotide Sequencing ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,3. Good health ,Pedigree ,030104 developmental biology ,HEK293 Cells ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,LDL receptor ,biology.protein ,lcsh:Q ,lipids (amino acids, peptides, and proteins) ,Female ,Proprotein Convertase 9 - Abstract
Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.
- Published
- 2018