title: Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia.
abstract: Aims Autosomal dominant hypercholesterolaemia (ADH) is a major risk factor for coronary artery disease. This disorder is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). However, in 41% of the cases, we cannot find mutations in these genes. In this study, new genetic approaches were used for the identification and validation of new variants that cause ADH.  Methods and results Using exome sequencing, we unexpectedly identified a novel APOB mutation, p.R3059C, in a small-sized ADH family. Since this mutation was located outside the regularly screened APOB region, we extended our routine sequencing strategy and identified another novel APOB mutation (p.K3394N) in a second family. In vitro analyses show that both mutations attenuate binding to the LDLR significantly. Despite this, both mutations were not always associated with ADH in both families, which prompted us to validate causality through using a novel genetic approach.  Conclusion This study shows that advances in genetics help increasing our understanding of the causes of ADH. We identified two novel functional APOB mutations located outside the routinely analysed APOB region, suggesting that screening for mutations causing ADH should encompass the entire APOB coding sequence involved in LDL binding to help identifying and treating patients at increased cardiovascular risk.
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands.
authors.forename: Mohammad Mahdi
authors.initials: MM
authors.lastname: Motazacker
authors.forename: James
authors.initials: J
authors.lastname: Pirruccello
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Jorge
authors.initials: J
authors.lastname: Peter
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases