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Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was co...

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Autores principales: Hu, Haochang, Shu, Tian, Ma, Jun, Chen, Ruoyu, Wang, Jian, Wang, Shuangshuang, Lin, Shaoyi, Chen, Xiaomin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712701/
https://www.ncbi.nlm.nih.gov/pubmed/34970301
http://dx.doi.org/10.3389/fgene.2021.762587
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author Hu, Haochang
Shu, Tian
Ma, Jun
Chen, Ruoyu
Wang, Jian
Wang, Shuangshuang
Lin, Shaoyi
Chen, Xiaomin
author_facet Hu, Haochang
Shu, Tian
Ma, Jun
Chen, Ruoyu
Wang, Jian
Wang, Shuangshuang
Lin, Shaoyi
Chen, Xiaomin
author_sort Hu, Haochang
collection PubMed
description As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.
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spelling pubmed-87127012021-12-29 Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia Hu, Haochang Shu, Tian Ma, Jun Chen, Ruoyu Wang, Jian Wang, Shuangshuang Lin, Shaoyi Chen, Xiaomin Front Genet Genetics As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR. Frontiers Media S.A. 2021-12-14 /pmc/articles/PMC8712701/ /pubmed/34970301 http://dx.doi.org/10.3389/fgene.2021.762587 Text en Copyright © 2021 Hu, Shu, Ma, Chen, Wang, Wang, Lin and Chen. 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
Hu, Haochang
Shu, Tian
Ma, Jun
Chen, Ruoyu
Wang, Jian
Wang, Shuangshuang
Lin, Shaoyi
Chen, Xiaomin
Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title_full Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title_fullStr Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title_full_unstemmed Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title_short Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
title_sort two novel disease-causing mutations in the ldlr of familial hypercholesterolemia
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712701/
https://www.ncbi.nlm.nih.gov/pubmed/34970301
http://dx.doi.org/10.3389/fgene.2021.762587
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