Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis

Hittitology today: Studies on Hittite and Neo-Hittite Anatolia in Honor of Emmanuel Laroche’s 100th Birthday

Il y a 100 ans, Emmanuel Laroche voyait le jour. Savant à la fois passionné de linguistique indo-européenne et d’Antiquité, il marqua durablement l’hittitologie par ses nombreuses contributions dans des domaines aussi variés que l’histoire des religions proche-orientales, la philologie cunéiforme ou encore la grammaire du hittite, du louvite et du hourrite. Ce colloque organisé en l’honneur de son centenaire a été l’occasion de faire le point sur les avancées de l’hittitologie actuelle, avancées auxquelles il participa tout au long de sa vie et qui se poursuivent après lui. Les axes thématiques qui sont abordés dans ce volume sont ceux qu’Emmanuel Laroche développa de son vivant, à savoir la linguistique des langues anatoliennes, la philologie et l’épigraphie cunéiforme et hiéroglyphique, les religions de l’Anatolie hittite et néo-hittite, l’histoire et la géographie historique, mais aussi l’archéologie proche-orientale, domaine qu’Emmanuel Laroche côtoya de près. Ajoutons à ces domaines celui de l’historiographie qui illustre, entre autres choses, l’impact des travaux d’Emmanuel Laroche dans l’hittitologie d’aujourd’hui.100 years ago, Emmanuel Laroche was born. As a scholar who was fascinated both by Indo-European Linguistics and Ancient Near Eastern and Classical Studies, he had a durable impact on Hittitology through his numerous contributions. His publications dealt with History of Near Eastern Religions, Cuneiform Philology, and Hittite, Luwian, and Hurrian grammar, among many other topics. This conference was organized in honor of his 100th birthday. Its aim was to discuss the recent developments in Hittitology, the ones to whom Emmanuel Laroche contributed and the ones which occurred after his time. The following themes are dealt with in this volume: Anatolian Linguistics, Cuneiform and Hieroglyphic Philology and Epigraphy, Religions of Bronze and Early Iron Age Anatolia, History and Historical Geography of Asia Minor, but also Near Eastern Archaeology, as Emmanuel Laroche was also very close to this discipline. Let us add to those fields Historiography which illustrates, among other things, the impact of Emmanuel Laroche’s work on today’s Hittitology

Organization of four mouse lambda light chain immunoglobulin genes.

We have cloned four lambda light chain constant region (C) genes from mouse embryo DNA. Each carries its own joining (J) segment approximately 1.3 kilobases to its 5' side. The four C genes occur in two clusters, 5' J3C3J1C13' and 5' J2C2J4C43', with C4 being a new C lambda gene. We have also shown that V lambda 1 is joined productively with C lambda 3 in a lambda 3-producing myeloma, and it is most likely that V lambda 1 and V lambda 2 are the only V lambda genes. Based on the analysis of the germ line and rearranged variable region (V) lambda genes in myelomas we argue that the V lambda 1 and V lambda 2 genes are at the 5' side of the C3C1 and C2C4 clusters, respectively. We propose that the two clusters arose by duplication. We also speculate on the role of J-associated DNA sequences in regulation of expression of the lambda subtypes

Exon shuffling generates an immunoglobulin heavy chain gene.

From endonuclease EcoRI partial libraries of DNAs from mouse embryo and MOPC 141, a gamma 2b-producing myeloma, clones were isolated by using a DNA fragment carrying the gamma 2b constant (C) region gene as a hybridization probe. One clone from MOPC 141 contained a heavy chain variable (V) gene and the C gamma 2b gene, as demonstrated by R-loop mapping. The V gene and C gene in this clone were separated by a 3.9-kilobase intron. The characterization of this clone as well as the embryonic clones suggest that at least two recombination events occurred to create the gamma 2b gene in MOPC 141. One of the events is analogous to the V-J joining previously demonstrated in the light chain genes, which brings the major part of the V gene next to a short coding sequence (J). The other event we refer to as "C mu-C gamma 2b switch recombination" because a portion of the intron between the V gene and C gene of the rearranged gamma 2b gene is derived from the 5' flanking sequence of the embryonic C mu gene. A model suggesting how the phenomenon of switch seen in lymphocytes may occur is presented