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Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia

We report a single-point variant of low-density lipoprotein receptor (LDLR) in a Chinese proband with a clinical diagnosis of familial hypercholesterolemia (FH) with a comprehensive functional analysis. Target exome capture-based next-generation sequencing was used for sequencing and identification...

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Autores principales: Shu, Hong-Yan, Zhang, Wei, Zheng, Cong-Cong, Gao, Man-Yun, Li, Yong-Cun, Wang, Yan-Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419346/
https://www.ncbi.nlm.nih.gov/pubmed/34497632
http://dx.doi.org/10.3389/fgene.2021.650077
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author Shu, Hong-Yan
Zhang, Wei
Zheng, Cong-Cong
Gao, Man-Yun
Li, Yong-Cun
Wang, Yan-Gang
author_facet Shu, Hong-Yan
Zhang, Wei
Zheng, Cong-Cong
Gao, Man-Yun
Li, Yong-Cun
Wang, Yan-Gang
author_sort Shu, Hong-Yan
collection PubMed
description We report a single-point variant of low-density lipoprotein receptor (LDLR) in a Chinese proband with a clinical diagnosis of familial hypercholesterolemia (FH) with a comprehensive functional analysis. Target exome capture-based next-generation sequencing was used for sequencing and identification of genomic variants in the LDLR gene. The expression, cellular location, and function of the mutant LDLR were analyzed. Sequencing of LDLR in FH patients indicated a point variant of single-base substitution (G < A) at a position of 2389 in the 16th exon, which led to a loss of the 16th exon in the LDLR messenger RNA. This genomic variant was found to cause exon 16 deletion in the mutant LDLR protein. Subsequent functional analyses showed that the mutant LDLR was retained in the Golgi apparatus and rarely expressed in the cellular membranes of HepG2 cells. Accordingly, the intake ability of HepG2 cells with the mutant LDLR was significantly reduced (P < 0.05). In conclusion, our results suggest that a mutant with a single-base substitution (c. 2389G > A) in the 16th exon of the LDLR gene was associated with miscleavage of messenger RNA and the retention of mutant LDLR in the Golgi apparatus, which revealed a pathogenic variant in LDLR underlying the pathogenesis of FH.
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spelling pubmed-84193462021-09-07 Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia Shu, Hong-Yan Zhang, Wei Zheng, Cong-Cong Gao, Man-Yun Li, Yong-Cun Wang, Yan-Gang Front Genet Genetics We report a single-point variant of low-density lipoprotein receptor (LDLR) in a Chinese proband with a clinical diagnosis of familial hypercholesterolemia (FH) with a comprehensive functional analysis. Target exome capture-based next-generation sequencing was used for sequencing and identification of genomic variants in the LDLR gene. The expression, cellular location, and function of the mutant LDLR were analyzed. Sequencing of LDLR in FH patients indicated a point variant of single-base substitution (G < A) at a position of 2389 in the 16th exon, which led to a loss of the 16th exon in the LDLR messenger RNA. This genomic variant was found to cause exon 16 deletion in the mutant LDLR protein. Subsequent functional analyses showed that the mutant LDLR was retained in the Golgi apparatus and rarely expressed in the cellular membranes of HepG2 cells. Accordingly, the intake ability of HepG2 cells with the mutant LDLR was significantly reduced (P < 0.05). In conclusion, our results suggest that a mutant with a single-base substitution (c. 2389G > A) in the 16th exon of the LDLR gene was associated with miscleavage of messenger RNA and the retention of mutant LDLR in the Golgi apparatus, which revealed a pathogenic variant in LDLR underlying the pathogenesis of FH. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8419346/ /pubmed/34497632 http://dx.doi.org/10.3389/fgene.2021.650077 Text en Copyright © 2021 Shu, Zhang, Zheng, Gao, Li and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Shu, Hong-Yan
Zhang, Wei
Zheng, Cong-Cong
Gao, Man-Yun
Li, Yong-Cun
Wang, Yan-Gang
Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title_full Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title_fullStr Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title_full_unstemmed Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title_short Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia
title_sort identification and functional characterization of a low-density lipoprotein receptor gene pathogenic variant in familial hypercholesterolemia
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419346/
https://www.ncbi.nlm.nih.gov/pubmed/34497632
http://dx.doi.org/10.3389/fgene.2021.650077
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