Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation

Backgrounds: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K). Objectives: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. Methods: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. Results: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93±2.95mmol/L, mean±SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06±4.96mmol/L) and compound heterozygous cases with LDLR mutations (14.84±1.62mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21±1.55mmol/L) were significantly lower than those (8.94±1.53mmol/L) in the hetero-FH by LDLR mutations. Conclusions: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations.