A Novel Thr56Met Mutation of the Autosomal Recessive Hypercholesterolemia Gene Associated with Hypercholesterolemia

Harada, Koji; Miyamoto, Yoshihiro; Morisaki, Hiroko; Ohta, Nobuhiro; Yamanaka, Itaru; Kokubo, Yoshihiro; Makino, Hisashi; Harada‐Shiba, Mariko; Okayama, Akira; Tomoike, Hitonobu; Okamura, Tomonori; Saito, Yoshihiko; Yoshimasa, Yasunao; Morisaki, Takayuki

doi:10.5551/jat.2873

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Recently, the mutation (T56M) of ARH has been associated with hypercholesterolemia (33). Thus far, this is the only point mutation identified on the PTB domain of ARH, but no effect on its binding to LDLR could be detected in a pull-down assay (34).…”

Section: Hypercholesterolemia-causing Mutations Destabilize the Arh-ldlrmentioning

confidence: 99%

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY 0 internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I -7 xF -5 xNPxY 0 QK +2 . The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y 0 ). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y 0 explains the distinctive ability of ARH to internalize proteins containing either FxNPxY 0 or FxNPxF 0 sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.lipoprotein | crystallography | trafficking | lipid metabolism

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Section: Hypercholesterolemia-causing Mutations Destabilize the Arh-ldlrmentioning

confidence: 99%

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…ARH is extremely rare compared to ADH, and the number of patients described to have defects in the ARH gene does not exceed 100 [32]. ARH was initially described in Sardinian and Lebanese families, but later found in American, Iranian, Japanese, Mexican, Asian, Indian, English, Turkish, and Syrian families [32-34]. …”

Section: Introductionmentioning

confidence: 99%

Familial Hypercholesterolemia: The Lipids or the Genes?

Fahed

Nemer

2011

Nutr Metab (Lond)

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Familial Hypercholesterolemia (FH) is a common cause of premature cardiovascular disease and is often undiagnosed in young people. Although the disease is diagnosed clinically by high LDL cholesterol levels and family history, to date there are no single internationally accepted criteria for the diagnosis of FH. Several genes have been shown to be involved in FH; yet determining the implications of the different mutations on the phenotype remains a hard task. The polygenetic nature of FH is being enhanced by the discovery of new genes that serve as modifiers. Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved. Because of this evolving polygenetic nature, the diagnosis of FH by genetic testing is hampered by its cost and effectiveness.In this review, we reconsider the clinical versus genetic nomenclature of FH in the literature. After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect. We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

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“…Despite the aforementioned, it is much less frequent to find cases of FH compared with ADH, the number of cases reported to date does not exceed 100 [ 70 ]. These cases have been found in Lebanese, Mexican, Japanese, Indian, English, Turkish, American and Syrian populations [ 71 , 72 ].…”

Section: Introductionmentioning

confidence: 99%

PCSK9 gene participates in the development of primary dyslipidemias

Matías-Pérez

Pérez-Santiago

Medina

et al. 2021

Balkan Journal of Medical Genetics

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Dyslipidemias are a group of diseases, which are characterized by abnormal blood concentrations of cholesterol, triglycerides and/or low-density lipoprotein-cholesterol (LDL-c). Dyslipidemia is a determinant condition for the progress of an atherosclerotic plaque formation. The resulting atherogenicity is due to at least two mechanisms: first, to the accumulation in the plasma of lipid particles that have the capacity to alter the function of the endothelium and deposit at the atheromatous plaque, and second, at an insufficient concentration of multifactorial type of high density lipoprotein-cholesterol (HDL-c), whose function is to protect against the development of atherosclerosis. Its highest prevalence is encountered among individuals with diabetes, hypertension or overweight. Hyperlipidemia is one of the main predisposing factors for the development of cardiovascular disease. Hyperlipidemia can be the result of a genetic condition, the secondary expression of a primary process or the consequence of exogenous factors (food, cultural, socio-economic, etc.), all of which lead to the elevation of plasma lipid levels. The objective of this study was to carry out an analysis of the genes involved in the development of dyslipidemias that lead to cardiovascular disease with special emphasis on the proprotein convertase subtilin/kexin type 9 (PCSK9) gene. The PCSK9 gene participates in the development of primary dyslipidemias, mainly familial hypercholesterolemia, currently the pharmacological treatment of choice to reduce LDL-c are statins, however, it has been observed that these have been insufficient to eliminate cardiovascular risk, especially in subjects with primary forms of hypercholesterolemia related to genetic mutations, or statin intolerance.

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A Novel Thr56Met Mutation of the Autosomal Recessive Hypercholesterolemia Gene Associated with Hypercholesterolemia

Cited by 8 publications

References 25 publications

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Familial Hypercholesterolemia: The Lipids or the Genes?

PCSK9 gene participates in the development of primary dyslipidemias

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