Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene

Barbagallo, Carlo M.; Emmanuele, Giovanni; Cefalù, Angelo B.; Fiore, Barbara; Noto, Davide; Mazzarino, María Clorinda; Pace, Andrea; Brogna, A.; Rizzo, Manfredi; Corsini, Alberto; Notarbartoló, A; Travali, Salvatore; Averna, Maurizio

doi:10.1016/s0021-9150(02)00379-9

Cited by 24 publications

(17 citation statements)

References 16 publications

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“…Primers for the study were as used previously. 10,11 PCR products were purified by Microcon (Millipore Corp, Bedford, MA) and used as templates for direct sequencing. DNA sequencing was carried out according to the manufacturer's instructions, using a dye terminator method (ABI PRISM 310 Genetic Analyzer (PerkinElmer Biosystems, Waltham, MA).…”

Section: Genetic Studiesmentioning

confidence: 99%

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Tada

Kawashiri

Ikewaki

et al. 2012

Circ Cardiovasc Genet

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Background-Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy. Methods and Results-We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [ 2 H 3 ]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450Ϯ0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2Ϯ2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months.Conclusions-These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1. (Circ Cardiovasc Genet. 2012;5:35-41.)Key Words: lipoproteins Ⅲ ARH Ⅲ genetics Ⅲ metabolism Ⅲ LDLRAP1 F amilial hypercholesterolemia (FH) is a common inherited disorder of plasma lipoprotein metabolism, characterized by an elevated level of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and premature coronary artery disease. 1 Genetic causes of FH involve gene mutations such as LDL receptor (LDLR), apolipoprotein B-100 (apoB-100), and proprotein convertase subtilisin/kexin type 9 (PCSK9). 2 In contrast, there was a report of autosomal recessive inherited cases, who showed elevation of LDL-C, large xanthomas, and premature coronary artery disease typical of homozygous FH but in whom the fibroblasts had normal LDLR function. 3 Subsequently, Garcia et al 4 showed that this disorder was caused by a recessive form of null mutations in the LDLR adaptor protein 1 (LDLRAP1). Clinical Perspective on p 41Since then, evidence has been accumulating that it was not linked to mutations in the LDLR gene. 5,6 The N-terminal domain of LDLRAP1 contains a phosphotyrosine-binding (PTB) domain, which binds to the internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR. 7 LDLRAP1 protein serves as an adaptor for LDLR endocytosis in the live...

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Section: Genetic Studiesmentioning

confidence: 99%

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Tada

Kawashiri

Ikewaki

et al. 2012

Circ Cardiovasc Genet

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“…In 2001, Garcia et al showed that this disorder is caused by a recessive form of null mutations in the LDLRAP1 gene 26) . Since then, 36 ARH families with 14 different mutations in the LDLRAP1 gene have been identified (Table 1), mostly from the island of Sardinia, where the frequency of a heterozygous mutation carrier status for the LDLRAP1 gene is estimated to be approximately 1 in 143 individuals [27][28][29][30][31][32][33][34] . We previously reported the second Japanese family with ARH in 2012 11)…”

Section: Clinical Significance Of a Heterozygous Mutation Carrier Stamentioning

confidence: 99%

Autosomal Recessive Hypercholesterolemia: A Mild Phenotype of Familial Hypercholesterolemia: Insight from the Kinetic Study using Stable Isotope and Animal Studies

Tada

Kawashiri

Nohara

et al. 2015

J Atheroscler Thromb

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“…At least five specific monogenic disorders, are known to be related to this phenomenon. These are familial hypercholesterolemia, familial ligand- Another form of FH, the ARH has been associated with the insertion mutation in a phosphotyrosine binding domain of the so-called ARH protein 55 , encoding a cellular adaptor protein required for LDL transport, and consequently for internalization of LDLs in the liver. This protein is thought to function as an adaptor protein that couples LDLR to the endocytotic machinery 36 .…”

Section: Pathways Regulating Lipid Metabolismmentioning

confidence: 99%

Gene Polymorphism and Coronary Heart Disease

Dzimiri¹

2012

Coronary Artery Disease - New Insights and Novel Approaches

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Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene

Cited by 24 publications

References 16 publications

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Autosomal Recessive Hypercholesterolemia: A Mild Phenotype of Familial Hypercholesterolemia: Insight from the Kinetic Study using Stable Isotope and Animal Studies

Gene Polymorphism and Coronary Heart Disease

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