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

Abstract

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 ± 2.95 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: Hiroshi Mabuchi, Atsushi Nohara, Tohru Noguchi, Junji Kobayashi, Masa-aki Kawashiri, Takeshi Inoue, Mika Mori, Hayato Tada, Chiaki Nakanishi, Kunimasa Yagi, Masakazu Yamagishi, Kousei Ueda, Tadayoshi Takegoshi, Susumu Miyamoto, Akihiro Inazu, Junji Koizumi, Hokuriku FH Study Group
• Journal: Atherosclerosis (Atherosclerosis) Vol. 236 Issue 1 Pg. 54-61 (Sep 2014) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25014035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Receptors, LDL
• Triglycerides
• Cholesterol
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Alleles
• Amino Acid Substitution
• Asian People (genetics)
• Cholesterol (blood)
• Cohort Studies
• DNA Mutational Analysis
• Female
• Gene Frequency
• Genes, Dominant
• Genetic Heterogeneity
• Genotype
• Homozygote
• Humans
• Hyperlipoproteinemia Type II (blood, epidemiology, genetics)
• Japan
• Male
• Mutation, Missense
• Pedigree
• Phenotype
• Point Mutation
• Proprotein Convertase 9
• Proprotein Convertases (genetics, physiology)
• Receptors, LDL (genetics)
• Serine Endopeptidases (genetics, physiology)
• Triglycerides (blood)