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

Mabuchi, Hiroshi; Nohara, Atsushi; Noguchi, Tohru; Kobayashi, Junji; Kawashiri, Masa‐aki; Inoue, Takeshi; Mori, Mika; Tada, Hayato; Nakanishi, Chiaki; Yagi, Kunimasa; Yamagishi, Masakazu; Ueda, Kousei; Takegoshi, Tadayoshi; Miyamoto, Susumu; Inazu, Akihiro; Koizumi, Junji

doi:10.1016/j.atherosclerosis.2014.06.005

Cited by 79 publications

(35 citation statements)

References 21 publications

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“…There are five classes of LDLR mutations: class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum; class 2 mutations prevent proper transport to the Golgi body; class 3 mutations stop the binding of LDL to the LDLRs; class 4 mutations inhibit the internalization of the LDLR-ligand complex, and class 5 mutations give rise to LDLRs that cannot recycle properly [12]. Moreover, there are also other genes involved in LDL metabolism, which mutations may result in a phenotype that is clinically indistinguishable from familial hypercholesterolemia such as apo B-100 (APOB-100), proprotein convertase subtilisin kexin type-9 (PCSK9), autosomal recessive hypercholesterolemia (ARH), cholesterol 7alpha-hydroxylase (CYP7A1) deficiencies, and others [13,14].…”

Section: Extreme Hypercholesterolemiamentioning

confidence: 99%

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Kolovou

Vasiliadis

Gontoras

et al. 2015

Cardiovascular Therapeutics

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SUMMARYThe genetic causes of cholesterol metabolism disorders usually lead to premature atherosclerosis. The most well recognized genetically caused hypercholesterolemia is familial hypercholesterolemia. Although the disease is well known, as the discovery of low-density lipoprotein receptor, the classical treatment with lipid-lowering drugs (statins, fibrates, ezetimibe, colesevelam) is still not adequate and new options are seeking. This review is an attempt to analyze the microsomal transfer protein (MTP) inhibitors as a new approach for treatment of familial hypercholesterolemia, to reviews the literature according to MTP inhibitors and finally to provide original findings.

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Section: Extreme Hypercholesterolemiamentioning

confidence: 99%

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Kolovou

Vasiliadis

Gontoras

et al. 2015

Cardiovascular Therapeutics

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“…DNA sequencing was carried out according to the manufacturer's instructions, using a dye terminator method, ABI PRISM™ 310 Genetic Analyzer (Applied Biosystems, Foster City, CA). We analysed ABCG5/ABCG8 genes as well as LDL receptor, PCSK9 and LDLRAP1 genes, as previously reported (Mabuchi et al 2014). In order to precisely determine the deleted codons in Case 1, Case 2 and Case 4, we digested the PCR products using DraI, which could recognise the 6-bp nucleotide TTTAAA and consequently make a 28-bp and an 85-bp fragment in the normal allele.…”

Section: Genetic Studiesmentioning

confidence: 99%

“…However, those manifestations responded very well to a variety of treatments, especially weaning from breastfeeding, which would not be observed in homozygous FH. Therefore, the aims of this study were (1) determining their molecular diagnosis, including LDL receptor, proprotein convertase subtilisin/ kexin type 9 (PCSK9) and LDL receptor adaptor protein 1 (LDLRAP1) genes that have been described as causative genes of Japanese FH (Mabuchi et al 2014) as well as ABCG5/8 genes as causes of Japanese sitosterolaemia (Tsubakio-Yamamoto et al 2010), and (2) evaluating their responsiveness to a variety of treatments.…”

Section: Introductionmentioning

confidence: 99%

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

et al. 2015

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Few data exists regarding the clinical impact of breastfeeding in infantile sitosterolaemic cases. We report four Japanese infantile cases of sitosterolaemia, an extremely rare inherited disease characterised by increased serum levels of plant sitosterol, presenting with severe hypercholesterolaemia and systemic xanthomas exacerbated by breastfeeding. In these four cases, genetic analyses were performed for low-density lipoprotein (LDL) receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein 1 and ATP-binding cassette (ABC) subfamily G member 5 and 8 (ABCG5 and ABCG8) genes. We assessed their clinical manifestations, including responsiveness to a variety of treatments, especially to weaning from breastfeeding and use of ezetimibe. Two pairs of mutations in the ABCG5 gene in each case, including two novel mutations (c.130C>T or p.Ser44Ala and c.1813_1817delCTTTT or p.Pro558GlufsX14) and two known mutations (c.1306G>A or p.Arg389His and c.1336C>T or p.Arg446X), were identified. Significant reductions in cholesterol levels were obtained by means of weaning from breastfeeding alone. Substantial reductions in sitosterol levels, without any apparent side effects, were observed with ezetimibe. In conclusion, we have identified infantile Japanese sitosterolaemic subjects with extreme hypercholesterolaemia exacerbated by breastfeeding. Their unique response to weaning from breastfeeding, as well as to use of ezetimibe, could provide insights into the metabolic basis of sterols in humans.

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“…In a Japanese study, 13/15 HoFH patients had LDLR gene mutations and 2/15 had PCSK9 gene mutations; among 10 HeFH patients with LDLR gene mutations, three patients also had PCSK9 gene mutations 25) . In 2014, a cohort of 1,055 HeFH patients and 41 HoFH patients was enrolled in a study in Japan 38) . Of all the HeFH patients, 993 carried the LDLR gene mutation and 62 had the PCSK9 E32K mutation.…”

Section: Genotypes Of Fh Reported In Asian Populationsmentioning

confidence: 99%

Familial Hypercholesterolemia in Asian Populations

Zhou

Zhao

2016

J Atheroscler Thromb

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Familial hypercholesterolemia (FH) is the most common autosomal disorder characterized by an elevated low-density lipoprotein-cholesterol level and a high risk of premature cardiovascular disease. In this review, we summarize information on FH studies in Asian countries, focusing on mean cholesterol level, FH frequency, diagnostic criteria, genotypes, and clinical care of FH patients in Asian populations. Compared with Western countries, most Asian countries had lower mean cholesterol levels, with a significant variation between different countries. In the limited studies reported, a frequency of 1/900 was reported in Hokuriku district, Japan in 1977 and a frequency of 1/85 among Christian Lebanese in 1979. Recently, a population study in China reported frequencies of 0.47% and 0.28%. However, the different FH frequencies reported were based on different diagnostic criteria. Of 28 publications from 16 Asian countries or regions, 14 used self-defined FH criteria. Only one specific guideline for FH was available, which was developed by Japanese scientists. Six Asian countries joined the Make Early Diagnosis to Prevent Early Deaths program in the late 1990s, and the estimated diagnosis rates of FH ranged from 3% to 10% in these countries. A more recent study explored the awareness, knowledge, and perception of FH among practitioners in Japan, Korea, and Taiwan. The study found that the correct rates of these FH-related questions were low and concluded that lack of country-specific criteria and guidelines may contribute to the lack of FH knowledge in the present survey. More attention and resources should be focused on raising awareness, improving care, and increasing FH research in Asian populations. J Atheroscler Thromb, 2016; 23: 539-549.

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

Cited by 79 publications

References 21 publications

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

Familial Hypercholesterolemia in Asian Populations

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