Affordable Access

deepdyve-link
Publisher Website

Functional analysis of six uncharacterised mutations in LDLR gene.

Authors
  • Gomez, Andrea1
  • Colombo, Roberto2
  • Pontoglio, Alessandro3
  • Helman, Lorena4
  • Kaeser, Luciana5
  • Giunta, Gustavo6
  • Parolin, Maria L7
  • Toscanini, Ulises5
  • Cuniberti, Luis8
  • 1 Favaloro University, Lipids and Atherosclerosis Laboratory - IMETTyB - CONICET, Buenos Aires, Argentina; PRICAI-Favaloro Foundation, Buenos Aires, Argentina. Electronic address: [email protected] , (Argentina)
  • 2 Niguarda Ca' Granda Metropolitan Hospital, Center for the Study of Rare Hereditary Diseases, Milan, Italy; Faculty of Medicine Catholic University of the Sacred Heart, IRCCS "Agostino Gemelli" University Hospital, Rome, Italy. , (Italy)
  • 3 Niguarda Ca' Granda Metropolitan Hospital, Center for the Study of Rare Hereditary Diseases, Milan, Italy. , (Italy)
  • 4 Favaloro Foundation University Hospital, Metabolic Unit Service, Buenos Aires, Argentina. , (Argentina)
  • 5 PRICAI-Favaloro Foundation, Buenos Aires, Argentina. , (Argentina)
  • 6 Favaloro University, Lipids and Atherosclerosis Laboratory - IMETTyB - CONICET, Buenos Aires, Argentina; Favaloro Foundation University Hospital, Metabolic Unit Service, Buenos Aires, Argentina. , (Argentina)
  • 7 Instituto de Diversidad y Evolución Austral. CCT Centpat-CONICET, Puerto Madryn, Argentina. , (Argentina)
  • 8 Favaloro University, Lipids and Atherosclerosis Laboratory - IMETTyB - CONICET, Buenos Aires, Argentina. , (Argentina)
Type
Published Article
Journal
Atherosclerosis
Publication Date
Dec 01, 2019
Volume
291
Pages
44–51
Identifiers
DOI: 10.1016/j.atherosclerosis.2019.10.013
PMID: 31689621
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Familial hypercholesterolemia (FH) is a primary hyperlipemia. It is an autosomal dominant genetic disorder of lipoproteins metabolism mainly caused by mutations in the low density lipoprotein receptor gene (LDLR). We aimed to investigate the functional impact on the low density lipoprotein receptor (LDLR) activity of six uncharacterised variants located in the coding region of the LDLR gene, namely c.428G > T, c.640T > C, c.1708C > T, c.1736A > T, c.1981C > G and c.2114C > G (NM_000527.4) and to attempt to define their clinical status. Functional studies were carried out using site-directed mutagenesis techniques and expression of LDLR protein in vitro. Results were correlated with clinical data and in silico analyses in order to assess the physiopathological role of these variants. This work provides functional information about 6 uncharacterised mutations in LDLR. The six variants studied here appeared to affect the LDLR function in vitro to different degrees, ranging from receptors with normal to slightly reduced activity to receptors exhibiting less than 10% of the wild-type activity. According to these studies and The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, two variants could be classified as "Likely Benign" (p.(Ala705Gly) and p.(Leu570Phe)), three variants as "Pathogenic" (p.(Asp579Val), p.(Cys143Phe) and p.(Trp214Arg)) and one variant as "Likely Pathogenic" (p.(Pro661Ala)). Copyright © 2019 Elsevier B.V. All rights reserved.

Report this publication

Statistics

Seen <100 times