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PNAS Papers Identify Splice Site Mutation in Immunodeficiency Condition, More

A team from France, Australia, Qatar, and the US describe an intronic STAT3 splice site mutation that contributes to an autosomal dominant primary immunodeficiency condition called hyper IgE syndrome (AD HIES) in seven affected individuals from a multi-generation, non-consanguineous French family. After failing to pick up characteristic exon-impacting slice site changes in STAT3 by targeted Sanger sequencing, the researchers did exome sequencing on three family members with AD HIES, followed by genome-wide family linkage analyses. Their search led to a chromosome 17 region harboring a heterozygous, intronic splice site change, which was subsequently found to produce a dominant-negative form of STAT3 that dials down the gene's level and related immune responses. "These findings highlight the importance of searching for deep intronic mutations in STAT3 before considering alternative genetic etiologies of HIES," the authors note.

German researchers explore human B lymphocyte changes over time following infection with the tumor-associated Epstein-Barr virus (EBV). By tracking phenotype, metabolism, and gene expression in EBV-infected and -uninfected human B lymphocyte cells over time with assays and RNA sequencing, the team teased out the timing and biological events involved as the infected lymphocytes morph to become more proliferative and prone to oncogenic transformation. "Our analysis suggests that the most profound alterations at the level of the cellular transcriptome of the infected naïve B lymphocyte occur within the first [three days], whereas phenotypic and metabolic features start changing from day [three] onwards," the authors report, noting that the data generated "are a rich source of cell biology covering the early molecular steps of B cell transformation driven by the tightly controlled expression program of viral genes."

Investigators in Canada, Sweden, and Germany share findings from a study of long, non-coding RNAs (lncRNAs) in human vascular inflammation, which contributes to atherosclerosis and other chronic inflammatory vascular conditions. Using expression arrays, the team compared lncRNA and messenger RNA levels before and after inflammatory cytokine exposure in vascular endothelial cells, identifying differential expression for 583 lncRNAs and 873 mRNAs. Through a series of follow-up experiments, the authors went on to characterize lncRNA-mRNA pairs, including a lncRNA that appears to influence expression of the proatherosclerotic chemokine-coding gene CCL2. They note that "lncRNA-CCL2 is relevant to human disease, as it is elevated in human atherosclerotic plaques, and, given its regulatory role, it may contribute to atherogenesis."