Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.     

Apolipoprotein L-I is the trypanosome lytic factor of human serum

Human sleeping sickness in east Africa is caused by the parasite Trypanosoma brucei rhodesiense. The basis of this pathology is the resistance of these parasites to lysis by normal human serum (NHS). Resistance to NHS is conferred by a gene that encodes a truncated form of the variant surface glycoprotein termed serum resistance associated protein (SRA). We show that SRA is a lysosomal protein, and that the amino-terminal alpha-helix of SRA is responsible for resistance to NHS. This domain interacts strongly with a carboxy-terminal alpha-helix of the human-specific serum protein apolipoprotein L-I (apoL-I). Depleting NHS of apoL-I, by incubation with SRA or anti-apoL-I, led to the complete loss of trypanolytic activity. Addition of native or recombinant apoL-I either to apoL-I-depleted NHS or to fetal calf serum induced lysis of NHS-sensitive, but not NHS-resistant, trypanosomes. Confocal microscopy demonstrated that apoL-I is taken up through the endocytic pathway into the lysosome. We propose that apoL-I is the trypanosome lytic factor of NHS, and that SRA confers resistance to lysis by interaction with apoL-I in the lysosome.     

Horizontal cell synapses onto glycine-accumulating interplexiform cells

Horizontal cells mediate lateral transmission of signals in the outer plexiform layer of the vertebrate retina, and are presumed to contribute to surround properties of photoreceptors and bipolar cells by chemical transmission. The cell bodies and dendrites of fish horizontal cells possess presynaptic specializations characteristic of conventional chemical synapses. Horizontal cell axon terminals have not so far been shown to contain presynaptic specializations nor have the targets of the somatic and dendritic synapses been fully characterized. Using electron microscope autoradiography of retinas labelled by high-affinity 3H-glycine uptake, we show here that goldfish horizontal cells make somatodendritic and axodendritic synapses on glycinergic interplexiform cells (Gly-IPCs) as apposed to dopaminergic interplexiform cells. Thus, horizontal cells have at least three postsynaptic targets: photoreceptors, bipolar cells and Gly-IPCs. Gly-IPCs may constitute a major alternative pathway for horizontal cell signals to reach the inner plexiform layer.     

Studies on the structure of collagen V. The site of binding of trivalent iron on collagen

Zusammenfassung Die Reaktion zwischen Kollagen und Fe^III wurde studiert. Es zeigte sich, dass das Eisen an die Sequenzen des Typs Ala-Asp-Gly gebunden wird. Weiter wurde gefunden, dass 1 mol Ratten-Tropokollagen 1 mol Cystein als Sequenz Cys-Ala-Asp-Gly enthält.

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S. Bump, Z. Deyl andJ. Rosmus, Communication IV, Experientia23, 518 (1967).     

A genome-wide association study identifies novel risk loci for type 2 diabetes

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.     

A microbial consortium couples anaerobic methane oxidation to denitrification

Modern agriculture has accelerated biological methane and nitrogen cycling on a global scale. Freshwater sediments often receive increased downward fluxes of nitrate from agricultural runoff and upward fluxes of methane generated by anaerobic decomposition. In theory, prokaryotes should be capable of using nitrate to oxidize methane anaerobically, but such organisms have neither been observed in nature nor isolated in the laboratory. Microbial oxidation of methane is thus believed to proceed only with oxygen or sulphate. Here we show that the direct, anaerobic oxidation of methane coupled to denitrification of nitrate is possible. A microbial consortium, enriched from anoxic sediments, oxidized methane to carbon dioxide coupled to denitrification in the complete absence of oxygen. This consortium consisted of two microorganisms, a bacterium representing a phylum without any cultured species and an archaeon distantly related to marine methanotrophic Archaea. The detection of relatives of these prokaryotes in different freshwater ecosystems worldwide indicates that the reaction presented here may make a substantial contribution to biological methane and nitrogen cycles.