title: Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.
abstract: BACKGROUND
  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).
  
  
  OBJECTIVE
  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 ± 2.95 mmol/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 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/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.
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan. Electronic address: mabuchi@med.kanazawa-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8640, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Kawashiri
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Mori
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakanishi
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yagi
authors.affiliation: Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Komatsu Municipal Hospital, Komatsu, Japan.
authors.forename: Kousei
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Fukui Prefectural Hospital, Fukui, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Takegoshi
authors.affiliation: Hokuriku Central Hospital, Oyabe, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Laboratory Science, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.affiliation: General Medicine, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Koizumi
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D018740:Genetic Heterogeneity; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D007564:Japan; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics* / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology; D014280:Triglycerides / Q000097:blood
chemical_list: D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Heterozygous-FH (Hetero-FH); Homozygous familial hypercholesterolemia (Homo-FH); LDL-receptor; PCSK9