title: Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.). s.w.fouchier@amc.uva.nl.
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.affiliation: From the Department of Experimental Vascular Medicine (S.W.F., J.C.M.M., J.C.D.), Department of Vascular Medicine (S.W.F., G.M.D.-T., J.J.P.K., G.K.H.), and Department of Medical Biochemistry (S.W.F., N.Z.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands (J.C.M.M.).
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001055:Apolipoproteins B; D011973:Receptors, LDL; C400186:STAP1 protein, human; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: STAP1 gene, human; hypercholesterolemia, autosomal dominant; physical chromosome mapping