The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.     

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Opioids block long-term potentiation of inhibitory synapses

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.     

Patterns of somatic mutation in human cancer genomes

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.     

High-redshift galaxy populations

We now see many galaxies as they were only 800 million years after the Big Bang, and that limit may soon be exceeded when wide-field infrared detectors are widely available. Multi-wavelength studies show that there was relatively little star formation at very early times and that star formation was at its maximum at about half the age of the Universe. A small number of high-redshift objects have been found by targeting X-ray and radio sources and most recently, gamma-ray bursts. The gamma-ray burst sources may provide a way to reach even higher-redshift galaxies in the future, and to probe the first generation of stars.     

ALCAM/CD166 adhesive function is regulated by the tetraspanin CD9

ALCAM/CD166 is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs) which mediates intercellular adhesion through either homophilic (ALCAM–ALCAM) or heterophilic (ALCAM–CD6) interactions. ALCAM-mediated adhesion is crucial in different physiological and pathological phenomena, with particular relevance in leukocyte extravasation, stabilization of the immunological synapse, T cell activation and proliferation and tumor growth and metastasis. Although the functional implications of ALCAM in these processes is well established, the mechanisms regulating its adhesive capacity remain obscure. Using confocal microscopy colocalization, and biochemical and functional analyses, we found that ALCAM directly associates with the tetraspanin CD9 on the leukocyte surface in protein complexes that also include the metalloproteinase ADAM17/TACE. The functional relevance of these interactions is evidenced by the CD9-induced upregulation of both homophilic and heterophilic ALCAM interactions, as reflected by increased ALCAM-mediated cell adhesion and T cell migration, activation and proliferation. The enhancement of ALCAM function induced by CD9 is mediated by a dual mechanism involving (1) augmented clustering of ALCAM molecules, and (2) upregulation of ALCAM surface expression due to inhibition of ADAM17 sheddase activity.     

Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics.

To test models of T-cell recognition, mice transgenic for T-cell receptor alpha or beta chain have been immunized with variant peptides that force changes in the resulting T-cell response. In particular, charge substitutions on the peptide often elicit reciprocal charges in the junctional (CDR3) sequences of T-cell receptor V alpha or V beta chains, indicating direct T-cell receptor-peptide contact, and allowing derivation of a topology for the T-cell receptor-MHC interaction. At one position on the peptide, variants transformed a homogeneous V beta response into a very heterogeneous one.     

Bose-Einstein condensates: microscopic magnetic-field imaging

Today's magnetic-field sensors are not capable of making measurements with both high spatial resolution and good field sensitivity. For example, magnetic force microscopy allows the investigation of magnetic structures with a spatial resolution in the nanometre range, but with low sensitivity, whereas SQUIDs and atomic magnetometers enable extremely sensitive magnetic-field measurements to be made, but at low resolution. Here we use one-dimensional Bose-Einstein condensates in a microscopic field-imaging technique that combines high spatial resolution (within 3 micrometres) with high field sensitivity (300 picotesla).     

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.     

Plants as a direct source of fuel

Summary Euphorbia lathyris, a plant which has been proposed as an energy farm candidate yields a total of 35% of its dry weight as simple organic extractables. Chemical analyses of the extracts show that 5% of the dry weight is a mixture of reduced terpenoids, in the form of triterpenoids, and 20% of the dry weight is simple sugars in the form of hexoses. The terpenoids can be converted to a gasoline-like substance and the sugars can be fermented to alcohol. Based on a biomass yield of about 25 dry tons ha^–1 year^–1, the total energy that can be obtained from this plant in the form of liquid fuels is 48 MJ ha^–1 year^–1, 26 MJ in the form of hydrocarbons and 22 MJ in the form of ethanol. A conceptual process study for the large scale recovery ofEuphorbia lathyris products indicates that this crop is a net energy producer. Several lines of investigation have been started to increase the hydrocarbon yield of this plant. Tissue cultures ofE. lathyris have been established and will be used for selection, with the aim of regenerating a superior plant. Biochemical studies have been initiated to elucidate regulation of terpenoid metabolism. Future plans include eventual genetic engineering to select the most desirable plant for hydrocarbon production.This work was supported by the Assistant Secretary for Conservation and Solar Energy, Office of Solar Energy, Solar Applications for Industry Division of the US Department of Energy under Contract No. W-7405-ENG-48.