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Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients

Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB varia...

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Autores principales: Rodríguez-Jiménez, Carmen, de la Peña, Gema, Sanguino, Javier, Poyatos-Peláez, Sara, Carazo, Ana, Martínez-Hernández, Pedro L., Arrieta, Francisco, Mostaza, José M., Gómez-Coronado, Diego, Rodríguez-Nóvoa, Sonia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142790/
https://www.ncbi.nlm.nih.gov/pubmed/37108800
http://dx.doi.org/10.3390/ijms24087635
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author Rodríguez-Jiménez, Carmen
de la Peña, Gema
Sanguino, Javier
Poyatos-Peláez, Sara
Carazo, Ana
Martínez-Hernández, Pedro L.
Arrieta, Francisco
Mostaza, José M.
Gómez-Coronado, Diego
Rodríguez-Nóvoa, Sonia
author_facet Rodríguez-Jiménez, Carmen
de la Peña, Gema
Sanguino, Javier
Poyatos-Peláez, Sara
Carazo, Ana
Martínez-Hernández, Pedro L.
Arrieta, Francisco
Mostaza, José M.
Gómez-Coronado, Diego
Rodríguez-Nóvoa, Sonia
author_sort Rodríguez-Jiménez, Carmen
collection PubMed
description Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB variants in patients with hypercholesterolemia. Index patients (n = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in LDLR, APOB, PCSK9 or LDLRAP1, with 12% of the variants in APOB. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants c.10030A>G;p.(Lys3344Glu) and c.11401T>A;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign.
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spelling pubmed-101427902023-04-29 Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients Rodríguez-Jiménez, Carmen de la Peña, Gema Sanguino, Javier Poyatos-Peláez, Sara Carazo, Ana Martínez-Hernández, Pedro L. Arrieta, Francisco Mostaza, José M. Gómez-Coronado, Diego Rodríguez-Nóvoa, Sonia Int J Mol Sci Article Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB variants in patients with hypercholesterolemia. Index patients (n = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in LDLR, APOB, PCSK9 or LDLRAP1, with 12% of the variants in APOB. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants c.10030A>G;p.(Lys3344Glu) and c.11401T>A;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign. MDPI 2023-04-21 /pmc/articles/PMC10142790/ /pubmed/37108800 http://dx.doi.org/10.3390/ijms24087635 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rodríguez-Jiménez, Carmen
de la Peña, Gema
Sanguino, Javier
Poyatos-Peláez, Sara
Carazo, Ana
Martínez-Hernández, Pedro L.
Arrieta, Francisco
Mostaza, José M.
Gómez-Coronado, Diego
Rodríguez-Nóvoa, Sonia
Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title_full Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title_fullStr Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title_full_unstemmed Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title_short Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
title_sort identification and functional analysis of apob variants in a cohort of hypercholesterolemic patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142790/
https://www.ncbi.nlm.nih.gov/pubmed/37108800
http://dx.doi.org/10.3390/ijms24087635
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