Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1784623611178385408 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8712701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT huhaochang twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT shutian twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT majun twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT chenruoyu twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT wangjian twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT wangshuangshuang twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT linshaoyi twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia AT chenxiaomin twonoveldiseasecausingmutationsintheldlroffamilialhypercholesterolemia |