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LDLR and PCSK9 3´UTR variants and their putative effects on microRNA molecular interactions in familial hypercholesterolemia: a computational approach
de Freitas, Renata Caroline Costa; Bortolin, Raul Hernandes; Borges, Jessica Bassani; de Oliveira, Victor Fernandes; Dagli-Hernandez, Carolina; Marçal, Elisangela da Silva Rodrigues; Bastos, Gisele Medeiros; Gonçalves, Rodrigo Marques; Faludi, Andre Arpad; Silbiger, Vivian Nogueira; Luchessi, André Ducati; Hirata, Rosario Dominguez Crespo; Hirata, Mario Hiroyuki.
Affiliation
  • de Freitas, Renata Caroline Costa; University of Sao Paulo. São Paulo. BR
  • Bortolin, Raul Hernandes; University of Sao Paulo. São Paulo. BR
  • Borges, Jessica Bassani; Hospital Beneficiência Portuguesa de São Paulo. São Paulo. BR
  • de Oliveira, Victor Fernandes; University of São Paulo. São Paulo. BR
  • Dagli-Hernandez, Carolina; University of São Paulo. São Paulo. BR
  • Marçal, Elisangela da Silva Rodrigues; University of São Paulo. Institute of Cardiology Dante Pazzanese. São Paulo. BR
  • Bastos, Gisele Medeiros; Hospital Beneficiencia Portuguesa de São Paulo. São Paulo. BR
  • Gonçalves, Rodrigo Marques; Institute of Cardiology Dante Pazzanese. São Paulo. BR
  • Faludi, Andre Arpad; Institute of Cardiology Dante Pazzanese. São Paulo. BR
  • Silbiger, Vivian Nogueira; Federal University of Rio Grande do Norte. Natal. BR
  • Luchessi, André Ducati; Federal University of Rio Grande do Norte. Natal. BR
  • Hirata, Rosario Dominguez Crespo; University of São Paulo. São Paulo. BR
  • Hirata, Mario Hiroyuki; University of São Paulo. São Paulo. BR
Mol. Biol. reports ; 50: 9165-9177, set.2023. ilus
Article in En | CONASS, SES-SP, SESSP-IDPCPROD, SES-SP | ID: biblio-1525357
Responsible library: BR79.1
ABSTRACT
BACKGROUND Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein 1 (LDLRAP1). However, approximately 40% of the FH patients clinically diagnosed (based on FH phenotypes) may not carry a causal variant in a FH-related gene. Variants located at 3' untranslated region (UTR) of FH-related genes could elucidate mechanisms involved in FH pathogenesis. This study used a computational approach to assess the effects of 3'UTR variants in FH-related genes on miRNAs molecular interactions and to explore the association of these variants with molecular diagnosis of FH. METHODS AND RESULTS Exons and regulatory regions of FH-related genes were sequenced in 83 FH patients using an exon-target gene sequencing strategy. In silico prediction tools were used to study the effects of 3´UTR variants on interactions between miRNAs and target mRNAs. Pathogenic variants in FH-related genes (molecular diagnosis) were detected in 44.6% FH patients. Among 59 3'UTR variants identified, LDLR rs5742911 and PCSK9 rs17111557 were associated with molecular diagnosis of FH, whereas LDLR rs7258146 and rs7254521 and LDLRAP1 rs397860393 had an opposite effect (p < 0.05). 3´UTR variants in LDLR (rs5742911, rs7258146, rs7254521) and PCSK9 (rs17111557) disrupt interactions with several miRNAs, and more stable bindings were found with LDLR (miR-4435, miR-509-3 and miR-502) and PCSK9 (miR-4796). CONCLUSION LDLR and PCSK9 3´UTR variants disturb miRNAmRNA interactions that could affect gene expression and are potentially associated with molecular diagnosis of FH.
Subject(s)

Full text: 1 Collection: 06-national / BR Database: CONASS / SES-SP / SESSP-IDPCPROD Main subject: MicroRNAs / Hyperlipoproteinemia Type II Language: En Journal: Mol. Biol. reports Year: 2023 Document type: Article

Full text: 1 Collection: 06-national / BR Database: CONASS / SES-SP / SESSP-IDPCPROD Main subject: MicroRNAs / Hyperlipoproteinemia Type II Language: En Journal: Mol. Biol. reports Year: 2023 Document type: Article