TY - JOUR
T1 - Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia
AU - Motazacker, Mohammad Mahdi
AU - Pirruccello, James
AU - Huijgen, Roeland
AU - Do, Ron
AU - Gabriel, Stacey
AU - Peter, Jorge
AU - Kuivenhoven, Jan Albert
AU - Defesche, Joep C.
AU - Kastelein, John J. P.
AU - Hovingh, G. Kees
AU - Zelcer, Noam
AU - Kathiresan, Sekar
AU - Fouchier, Sigrid W.
PY - 2012
Y1 - 2012
N2 - 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. 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. 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
AB - 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. 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. 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
U2 - https://doi.org/10.1093/eurheartj/ehs010
DO - https://doi.org/10.1093/eurheartj/ehs010
M3 - Article
C2 - 22408029
SN - 0195-668X
VL - 33
SP - 1360
EP - 1366
JO - European Heart journal
JF - European Heart journal
IS - 11
ER -