A new variant (c.1A&gt;G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition

Rodríguez-Jiménez, Carmen; Gómez-Coronado, Diego; Vargas, Manuel Frías; Cerrato, Francisca; Lahoz, Carlos; Sabán-Ruiz, J.; González‐Nieto, Daniel; Lasunción, Miguel A.; Mostaza, José María; Rodrı́guez-Nóvoa, Sonia

doi:10.1016/j.atherosclerosis.2019.01.010

Cited by 10 publications

(5 citation statements)

References 39 publications

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“…However, even in the absence of the ARH protein, PCSK9 still resulted in a decrease in the level of LDLR [16]. Treatment with evolocumab further decreased the LDL-C levels in ARH patients with very low levels of cell surface LDLR internalization [17,18]. These findings are indicative of the existence of an ARH-independent intracellular approach for the PCSK9-mediated degradation of LDLR.…”

Section: Intracellular Endogenous Pcsk9-induced Ldlr Degradationmentioning

confidence: 87%

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Tang

et al. 2020

Cardiovasc Diabetol

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The proprotein convertase subtilisin/kexin type 9 (PCSK9) acts via a canonical pathway to regulate circulating lowdensity lipoprotein-cholesterol (LDL-C) via degradation of the LDL receptor (LDLR) on the liver cell surface. Published research has shown that PCSK9 is involved in atherosclerosis via a variety of non-classical mechanisms that involve lysosomal, inflammatory, apoptotic, mitochondrial, and immune pathways. In this review paper, we summarized these additional mechanisms and described how anti-PCSK9 therapy exerts effects through these mechanisms. These additional pathways further illustrate the regulatory role of PCSK9 in atherosclerosis and offer an in-depth interpretation of how the PCSK9 inhibitor exerts effects on the treatment of atherosclerosis.

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Section: Intracellular Endogenous Pcsk9-induced Ldlr Degradationmentioning

confidence: 87%

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Tang

et al. 2020

Cardiovasc Diabetol

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“…Genomic DNA was extracted from peripheral blood according to standard protocols (12). A gene panel-based next-generation sequencing (NGS) was performed to nd casual variant(s) in the known involved genes of FH, including LDLR, LDLRAP1, PCSK9 and APOB (13). PCR primers were designed for the target region of LDLRAP1 gene and the target region was ampli ed according to a conventional protocol.…”

Section: Methodsmentioning

confidence: 99%

An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

Nikasa

Rabbani

Hejazi

et al. 2021

Preprint

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Background: Autosomal recessive hypercholesterolemia (ARH) is a rare monogenic disorder resulting from mutations of the LDLRAP1 gene, which leads to elevated LDL-C levels. Here, using whole exome sequencing (WES), we describe a 22-year-old Iranian female who carries a novel nonsense mutation in LDLRAP1. Methods: Genetic investigations were performed for the patient and her family. She showed LDL-C level of 720 mg/dL since the age of 11 years. At the age of 13 years old, aortic valve repair surgery was performed due to severe aortic valve stenosis (AVS). At the age of 17, along with prescription of rosuvastatin plus ezetimibe, coronary angiography displayed the presence of serious stenotic lesions of the coronary arteries and also aortic valve, making the patient eligible for coronary artery bypass grafting (CABG) and aortic valve replacement (AVR).Results: Genetic analysis showed the presence of a previously unreported homozygous LDLRAP1 gene variant, c.649G>T, generating a nonsense mutation at amino acid 217, shortening the ARH protein from 308 to 217 amino acid, which removes AP-2 binding domain of ARH, as an important part in LDL uptake.Conclusion: During a 10-year treatment, we observed a 74% reduction in LDL-C level. Despite the treatment with maximal dose of rosuvastatin plus ezetimibe, the results of coronary angiography demonstrated severe supravalvular aortic stenosis (SVAS) resulted in significant stenotic lesions of the coronary arteries and aortic valve. This highlights the importance of WES in early diagnosis of ARH, and it is proposed to prevent or at least delay the onset of the cardiovascular events.

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“…Furthermore, the measurement of LDLR activity was carried out by incubating the patient's peripheral blood lymphocytes with different concentrations of human DiI-labeled LDL at 4°C (binding) or 37°C (uptake) and subsequent analysis by flow cytometry as previously described. [ 5 ]…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, mutations in LDLRAP1 (MIM# 605747) cause an autosomal recessive form of FH (ARH), which also has low prevalence. [ 5 ]…”

Section: Introductionmentioning

confidence: 99%

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia

et al. 2020

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Rationale: Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events. Patient concerns: We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia. Diagnosis: Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [ exon 6:c.902A>G: p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [ exon1:c.137 G>T: p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [ c.902A>G: p.(Asp301Gly); c.1646G>T: p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [( PCSK9:exon1:c.137G>T: p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter. Interventions: The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control. Outcomes: To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication. Lessons: Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations ( LDLR-PCSK9 ) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.

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A new variant (c.1A>G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition

Cited by 10 publications

References 39 publications

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia

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