Mutations in STAP1 are Associated With Autosomal Dominant Hypercholesterolemia
Rationale: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and increased risk for coronary artery disease (CAD). ADH is caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin 9 (PCSK9). However, in a proportion of ADH cases mutations in these genes are not found.
Objective: To identify a fourth locus associated with ADH.
Methods and Results: Parametric linkage analysis combined with exome sequencing in a FH4 family resulted in the identification of the variant p.Glu97Asp in STAP1, encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands, in which mutations in the established LDL-associated genes were ruled out, identified a second p.Glu97Asp carrier and three additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (N=40) showed significantly higher plasma total cholesterol and LDL-c levels compared to non-affected relatives (N=91).
Conclusions: We mapped a novel ADH locus at 4p13, and identified four variants in STAP1 that associate with ADH.
- exome sequencing
- genetic mapping
- cholesterol metabolism
- genetics, human
- genetics, linkage analysis
- cardiovascular disease risk factors
- cholesterol homeostasis
- Received June 22, 2014.
- Revision received July 15, 2014.
- Accepted July 16, 2014.