Mutation screening of MIR146A/B and XXXX /2 3'-UTRs in the GENESIS study.

@entity1 @entity0 @entity5344 @entity5345 @entity2674 @entity38113 @entity6991
UNASSIGNED: Although a wide number of @entity0 susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major @entity5345 and @entity2674 genes are being extensively screened for truncating and missense variants in @entity5344 families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, @entity6991 and @entity38113 , producing @entity6991 and miR-146b-5p, respectively, that regulate @entity5345 , and the 3'- untranslated regions (3'-UTRs) of @entity5345 and @entity2674 in the GENESIS French national case/control study ( @entity5345 - and @entity2674 -negative @entity0 cases with at least one sister with @entity0 and matched controls). We identified one rare variant in @entity6991 , four in @entity38113 , five in @entity5345 3'-UTR and one in @entity2674 3'-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant @entity6991 / @entity38113 variants affected the pre-miR sequences. The potential causality of the four relevant @entity5345 / @entity2674 3'-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of @entity2674 3'-UTR in a large series of @entity0 cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.European Journal of @entity1 Genetics advance online publication, 20 January 2016; doi:10.1038/ejhg.2015.284.
