LDLR and PCSK9 3´UTR variants and their putative effects on microRNA molecular interactions in familial hypercholesterolemia: a computational approach
Mol. Biol. reports
; 50: 9165-9177, set.2023. ilus
Artigo
em Inglês
| CONASS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP
| ID: biblio-1525357
Biblioteca responsável:
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.
Texto completo:
Disponível
Coleções:
Bases de dados nacionais
/
Brasil
Base de dados:
CONASS
/
Sec. Est. Saúde SP
/
SESSP-IDPCPROD
Assunto principal:
MicroRNAs
/
Hiperlipoproteinemia Tipo II
Idioma:
Inglês
Revista:
Mol. Biol. reports
Ano de publicação:
2023
Tipo de documento:
Artigo
Instituição/País de afiliação:
Federal University of Rio Grande do Norte/BR
/
Hospital Beneficiencia Portuguesa de São Paulo/BR
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Hospital Beneficiência Portuguesa de São Paulo/BR
/
Institute of Cardiology Dante Pazzanese/BR
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University of Sao Paulo/BR
/
University of São Paulo/BR