Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of...

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Detalles Bibliográficos
Autores: Rodríguez-Jiménez, Carmen, Pernía, Olga, Mostaza, Jose, Rodríguez-Antolín, Carlos, García Díaz, Juan de Dios, Alonso Cerezo, Concepción, García-Polo, Iluminada, Blanco, Agustín, Lahoz, Carlos, Arrieta, Francisco, Beltrán, Luis, Díaz de Bustamante, Ana, Garzón-Lorenzo, Lucía, Álvarez-Sala, Luis Antonio, Asenjo, Ángel, Ibáñez de Cáceres, Inmaculada, Rodríguez -Nóvoa, Sonia
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad Francisco de Vitoria
Repositorio:DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
Idioma:inglés
OAI Identifier:oai:ddfv.ufv.es:10641/5506
Acceso en línea:https://hdl.handle.net/10641/5506
Access Level:acceso abierto
Palabra clave:Familial hypercholesterolemia
Functional study
Genetic variants
LDLR gene
Descripción
Sumario:Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as “uncertain significant variants”, and therefore, carry out cascade family screening.

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