Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome

We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy.     

A stomatin-domain protein essential for touch sensation in the mouse

Touch and mechanical pain are first detected at our largest sensory surface, the skin. The cell bodies of sensory neurons that detect such stimuli are located in the dorsal root ganglia, and subtypes of these neurons are specialized to detect specific modalities of mechanical stimuli. Molecules have been identified that are necessary for mechanosensation in invertebrates but so far not in mammals. In Caenorhabditis elegans, mec-2 is one of several genes identified in a screen for touch insensitivity and encodes an integral membrane protein with a stomatin homology domain. Here we show that about 35% of skin mechanoreceptors do not respond to mechanical stimuli in mice with a mutation in stomatin-like protein 3 (SLP3, also called Stoml3), a mammalian mec-2 homologue that is expressed in sensory neurons. In addition, mechanosensitive ion channels found in many sensory neurons do not function without SLP3. Tactile-driven behaviours are also impaired in SLP3 mutant mice, including touch-evoked pain caused by neuropathic injury. SLP3 is therefore indispensable for the function of a subset of cutaneous mechanoreceptors, and our data support the idea that this protein is an essential subunit of a mammalian mechanotransducer.     

Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.     

The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system

Blood vessels and nerves are complex, branched structures that share a high degree of anatomical similarity. Guidance of vessels and nerves has to be exquisitely regulated to ensure proper wiring of both systems. Several regulators of axon guidance have been identified and some of these are also expressed in endothelial cells; however, the extent to which their guidance functions are conserved in the vascular system is still incompletely understood. We show here that the repulsive netrin receptor UNC5B is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice, or of Unc5b or netrin-1a in zebrafish, leads to aberrant extension of endothelial tip cell filopodia, excessive vessel branching and abnormal navigation. Netrin-1 causes endothelial filopodial retraction, but only when UNC5B is present. Thus, UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system.     

IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics

Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.     

MgCo2-D2 and MgCoNi-D2 systems synthesized at high pressures and interaction mechanism during the HDDR processing

MgCo_2 and MgNiCo crystallize with hexagonal Laves type intermetallic structures of the C14 type and do not form hydrides at ambient hydrogen pressures. However, applying high hydrogen pressures in the GPa range forces the hydrogen absorption and leads to the formation of multi-phase compositions, which contain approximately 2.5 atoms H per formula unit of MgCo_2 or MgNiCo and remain thermally stable under normal conditions.The hydrogenation of MgCo_2 resulted in its decomposition to a ternary Mg_2CoD_5 deuteride and metallic cobalt. Phase-structural transformations accompanying the vacuum desorption of deuterium in the temperature range of 27–500 °C were studied using in situ neutron powder diffraction. The investigation showed a complete recovery of the initial MgCo_2 intermetallic via a Hydrogenation-Disproportionation-Desorption-Recombination process. At 300°C, the Mg_2CoD_5 deuteride first decomposed to elementary Mg and hexagonal Co. At 400°C, a MgCo phase was formed by interaction between Mg and Co. At the highest processing temperature of 500°C, a solid-state interaction of MgCo and Co resulted in the recovery of the initial MgCo_2.The interaction of MgNiCo with deuterium under the synthesis conditions of 2.8 GPa and 200 °C proceeded in a more complex way. A very stable ternary deuteride MgNi_2D_3 was leached away while Co was separated in the form of Mg_2CoD_5 and the remaining nickel formed a solid solution with Co with the approximate composition Ni_(0.7)Co_(0.3).The thermal desorption of deuterium from MgCo_2D_(2.5) and from MgNiCoD_(2.5) has been studied by Thermal Desorption Spectroscopy with deuterium released into a closed volume. The observed effects nicely correlate with changes in the phase structural composition of the hydrides formed.MgCo_2 is a new example of the hydrogen storage alloy, in which a successful HDDR processing results in the reversible formation of the initial intermetallic at much lower temperatures than in the equilibrium phase diagram of the Mg-Co system.