Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.
Complement is an important component of the innate immune system, which collaborates with the adaptive antibody immune system. It is activated through three different pathways, which all trigger cleavage of the three homolgous proteins C3, C4 and C5. The latter is cleaved into the small anaphylatoxin C5a and the large C5b fragment. C5a binds to two G-protein coupled receptors and thereby elicit chemotaxis, a respiratory burst, and release of proinflammatory mediators. C5b combine with four other complement proteins to form the membrane perforating membrane attack complex. To provide the structural basis of the functions of C5, we have determined the crystal structure of human C5 at 3.1 Å resolution [1]. In addition we have studied the interaction of C5 with inhibitors. The structure of C5 will be presented and the potential for using structural data in therautic approaches to diseases involving complement will be discussed.
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