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

• Published in: Atherosclerosis Vol. 292; pp. 143 - 151
• Main Authors: Lamiquiz-Moneo, Itziar, Restrepo-Córdoba, María Alejandra, Mateo-Gallego, Rocío, Bea, Ana María, del Pino Alberiche-Ruano, María, García-Pavía, Pablo, Cenarro, Ana, Martín, Cesar, Civeira, Fernando, Sánchez-Hernández, Rosa María
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-01-2020
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adolescent; Adult; Aged; Familial hypercholesterolemia; Family cosegregation; Female; Humans; Hyperlipoproteinemia Type II - diagnosis; Hyperlipoproteinemia Type II - genetics; Male; Middle Aged; Mutation; Mutation-negative familial hypercholesterolemia; Pedigree; STAP1; Young Adult; STAP1; Family cosegregation; Familial hypercholesterolemia; Mutation-negative familial hypercholesterolemia
• DOI: 10.1016/j.atherosclerosis.2019.11.025
• EISSN: 1879-1484
• ISSN: 0021-9150

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.
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.
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.
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.
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•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.