Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene

Substitutions of single glycine residues of alpha 1(I) collagen have previously been associated with the inherited disease osteogenesis imperfecta type II. Transgenic mice bearing a mutant alpha 1(I) collagen gene into which specific glycine substitutions have been engineered show a dominant lethal phenotype characteristic of the human disease, and demonstrate that as little as 10% mutant gene expression can disrupt normal collagen function.     

Unusual antimicrobial compounds fromAeollanthus buchnerianus

Using bioassay guided isolation, three novel 12 carbon polyoxygenated fatty acids and a novel abietane diterpene have been isolated from the the chloroform extract of aerial parts ofAeollanthus buchnerianus (Lamiaceae). Rigorous spectroscopic methods were used for compound identification. (Z,Z)-8-acetoxy-5-hydroxydodeca-2,6-dienoic acid and (Z,Z)-5,8-dihydroxydodeca-2,6-dienoic acid inhibited the spore germination ofCladosporium cucumerinum (both with Minimum Inhibitory Dose (MID) values of 1 g) andAspergillus niger (MID 5 and 25 g respectively). Further, they also reduced the hyphal growth ofPythium ultimum. (Z)-5-hydroxy-6,7,8-triacetoxydodeca-2-dienoic acid exhibited short term inhibition of the growth ofCladosporium cucumerinum. The novel abietane diterpenoid, (rel)-14-acetoxyabiet-7-en-18-oic acid inhibited the growth of the gram positive bacteriaBacillus subtilis, staphylococcus aureus andStreptomyces scabies (MIC values 80, 20 and 20 g ml^–1 respectively).     

Pathogenic mutation in the ALS/FTD gene, <Emphasis Type="Italic">CCNF,</Emphasis> causes elevated Lys48-linked ubiquitylation and defective autophagy

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCF^{cyclin F}) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin F^S621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin F^WT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin F^S621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin F^S621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin F^S621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis.     

Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth

17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

Botany: specialized bird perch aids cross-pollination

Birds may hover over or perch on flowers when feeding on nectar, and this assists cross-pollination if they then visit other plants. Here we investigate the curious sterile inflorescence axis of the South African Cape endemic 'rat's tail' plant (Babiana ringens, Iridaceae), whose function--unlike in other bird-pollinated plants--is exclusively to provide a perch for foraging birds. We find that this structure promotes the plant's mating success by causing the malachite sunbird (Nectarinia famosa), its main pollinator, to adopt a position ideal for the cross-pollination of its unusual ground-level flowers.     

An SNP map of human chromosome 22

The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.     

Effects of disodium EDTA on the cardiovascular responses to prostaglandin E1

Zusammenfassung Die Wirkung des Dinatrium-EDTA auf die Kreislaufreaktionen des Prostaglandin E₁ (PGE₁) wurde an narkotisierten Hunden untersucht. Das Ausmass der positiv chronotropen und inotropen Einflüsse des PGE₁ war während der Infusion von EDTA bedeutend geringer als das des PGE₁ vor der EDTA-Gabe. Die Gegenwart oder das Einströmen von Kalziumionen scheint in der pharmakologischen Wirkung des PGE₁ eine Rolle zu spielen.