Sigrid W Fouchier1, Geesje M Dallinga-Thie2, Joost C M Meijers2, Noam Zelcer2, John J P Kastelein2, Joep C Defesche2, G Kees Hovingh2. 1. 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. 2. 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.).
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.
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.
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