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Predicted pathogenic mutations in STAP1 are not associated with clinically defined familial hypercholesterolemia

  • Itziar Lamiquiz-Moneo
    Correspondence
    Corresponding author. Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Avenida Isabel La Católica, 1-3, 50009, Zaragoza, Spain.
    Affiliations
    Lipid Unit, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBER Cardiovascular (CIBERCV), Zaragoza, Spain
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  • María Alejandra Restrepo-Córdoba
    Affiliations
    Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBER Cardiovascular (CIBERCV), Madrid, Spain
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  • Rocío Mateo-Gallego
    Affiliations
    Lipid Unit, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBER Cardiovascular (CIBERCV), Zaragoza, Spain

    Universidad de Zaragoza, Zaragoza, Spain
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  • Ana María Bea
    Affiliations
    Lipid Unit, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBER Cardiovascular (CIBERCV), Zaragoza, Spain
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  • María del Pino Alberiche-Ruano
    Affiliations
    Endocrinology Department, Hospital Universitario Insular de Gran Canaria, Instituto Universitario de Investigación Biomédica y de la Salud de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
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  • Pablo García-Pavía
    Affiliations
    Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBER Cardiovascular (CIBERCV), Madrid, Spain

    Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain
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  • Ana Cenarro
    Affiliations
    Lipid Unit, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBER Cardiovascular (CIBERCV), Zaragoza, Spain
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  • Cesar Martín
    Affiliations
    Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain
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  • Fernando Civeira
    Affiliations
    Lipid Unit, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBER Cardiovascular (CIBERCV), Zaragoza, Spain

    Universidad de Zaragoza, Zaragoza, Spain
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  • Rosa María Sánchez-Hernández
    Affiliations
    Endocrinology Department, Hospital Universitario Insular de Gran Canaria, Instituto Universitario de Investigación Biomédica y de la Salud de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
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      Highlights

      • STAP1 has been proposed as a candidate gene for FH with controversial results.
      • Predicted pathogenic mutations in STAP1 in genetic negative FH were studied.
      • These mutations in STAP1 did not cosegregate with hypercholesterolemia in families.
      • STAP1 does not seem to play a major role in the etiology of FH.

      Abstract

      Background and aims

      Autosomal dominant familial hypercholesterolemia (FH) is caused by mutations in LDLR, APOB and PCSK9. Two new putative loci causing FH have been identified recently, the p.(Leu167del) mutation in APOE and new mutations in the signal transducing adaptor family member STAP1. We aimed at investigating the role of STAP1 mutations in the etiology of FH.

      Methods

      We sequenced LDLR, APOB, PCSK9, LDLRAP1, APOE, LIPA and STAP1 with the LipidInCode platform in 400 unrelated subjects from Spain with a clinical diagnosis of FH. All subjects carrying rare predicted pathogenic variants in STAP1 gene, described as pathogenic by at least three bioinformatic analysis and having an allelic frequency lower than 1% in general population, were selected for family study. Available relatives were recruited, including both hypercholesterolemic and non-hypercholesterolemic family members.

      Results

      Sequencing analysis of STAP1 gene revealed seventeen rare variants, four of them being described as pathogenic by bioinformatic analysis. We studied the cosegregation with hypercholesterolemia of four rare predicted pathogenic variants, c.-60A > G, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) in seven families. We did not observe any cosegregation between genotype and phenotype, even carriers of rare variants in STAP1 had lower LDL cholesterol levels than non-carriers.

      Conclusions

      This study analyzes the family cosegregation of four rare predicted pathogenic variants of STAP1, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) and c.-60A > G, in seven families, showing absence of cosegregation in all of them. These results would suggest that STAP1 gene is not involved in hypercholesterolemia of these families.

      Graphical abstract

      Keywords

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