Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia.

Abstract

RATIONALE:

Autosomal-dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and increased risk for coronary vascular disease. ADH is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin 9. A number of patients, however, suffer from familial hypercholesterolemia 4 (FH4), defined as ADH in absence of mutations in these genes and thereafter use the abbreviation FH4.

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 signal transducing adaptor family member 1 (STAP1), encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands identified a second p.Glu97Asp carrier and 3 additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (n=40) showed significantly higher plasma total cholesterol and low-density lipoprotein cholesterol levels compared with nonaffected relatives (n=91).

CONCLUSIONS:

We mapped a novel ADH locus at 4p13 and identified 4 variants in STAP1 that associate with ADH.

• Authors: Sigrid W Fouchier, Geesje M Dallinga-Thie, Joost C M Meijers, Noam Zelcer, John J P Kastelein, Joep C Defesche, G Kees Hovingh
• Journal: Circulation research (Circ Res) Vol. 115 Issue 6 Pg. 552-5 (Aug 29 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 25035151 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Apolipoproteins B
• Receptors, LDL
• STAP1 protein, human
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Apolipoproteins B (genetics)
• Female
• Genetic Linkage
• Humans
• Hyperlipoproteinemia Type II (genetics, metabolism, physiopathology)
• Lipid Metabolism (physiology)
• Male
• Middle Aged
• Mutation (genetics)
• Proprotein Convertase 9
• Proprotein Convertases (genetics)
• Receptors, LDL (genetics)
• Serine Endopeptidases (genetics)