Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes may overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective To investigate the ability of whole-exome screening methods to detect disease-causing variants in individuals with PIDDs. Methods Individuals with PIDDs from 278 families from 22 countries were investigated using whole-exome sequencing (WES). Computational CNV prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic copy number variants (CNVs). Analytic approaches initially focused on 475 known or candidate PIDD genes, but were non-exclusive and were further tailored based upon clinical data, family history and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on the molecular findings. Twelve PIDD-causing CNVs were detected, including seven smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes, permitted detection of low-grade constitutional, somatic and revertant mosaicism, and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
Specific metabolic underpinnings of androgen receptor (AR)-driven growth in prostate adenocarcinoma (PCa) are largely undefined, hindering the development of strategies to leverage the metabolic dependencies of this disease when hormonal manipulations fail. Here we show that the mitochondrial pyruvate carrier (MPC), a critical metabolic conduit linking cytosolic and mitochondrial metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition restricts proliferation and metabolic outputs of the citric acid cycle (TCA) including lipogenesis and oxidative phosphorylation in AR-driven PCa models. Mechanistically, metabolic disruption resulting from MPC inhibition activates the eIF2α/ATF4 integrated stress response (ISR). ISR signaling prevents cell cycle progression while coordinating salvage efforts, chiefly enhanced glutamine assimilation into the TCA, to regain metabolic homeostasis. We confirm that MPC function is operant in PCa tumors in-vivo using isotopomeric metabolic flux analysis. In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumor growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumors.
Organized by unstructured motifs The high degree of conservation in protein sequences thought to be unstructured has hinted that these regions may have important biological functions. Although unstructured regions are widely viewed to be crucial for protein signaling, localization, and stability, their roles in many other settings have remained mysterious. Cermakova et al . discovered that prominent members of the transcription elongation machinery are linked through a network of interactions involving transcription elongation factor TFIIS N-terminal domains (TNDs) and conserved unstructured sequences called “TND-interacting motifs” (TIMs). The researchers found that mutation of a single TIM in a central organizing protein of this network abolished key protein interactions and induced widespread defects in transcription elongation dynamics. —DJ
MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.
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