Singlet-Oxygen Generation by Peroxidases and Peroxygenases for Chemoenzymatic Synthesis

Singlet oxygen is a reactive oxygen species undesired in living cells but a rare and valuable reagent in chemical synthesis. We present a fluorescence spectroscopic analysis of the singlet-oxygen formation activity of commercial peroxidases and novel peroxygenases. Singlet-oxygen sensor green (SOSG) is used as fluorogenic singlet oxygen trap. Establishing a kinetic model for the reaction cascade to the fluorescent SOSG endoperoxide permits a kinetic analysis of enzymatic singlet-oxygen formation. All peroxidases and peroxygenases show singlet-oxygen formation. No singlet oxygen activity could be found for any catalase under investigation. Substrate inhibition is observed for all reactive enzymes. The commercial dye-decolorizing peroxidase industrially used for dairy bleaching shows the highest singlet-oxygen activity and the lowest inhibition. This enzyme was immobilized on a textile carrier and successfully applied for a chemical synthesis. Here, ascaridole was synthesized via enzymatically produced singlet oxygen. © 2020 Wiley-VCH Gmb

A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32

Background: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family.Methods: Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations. Results: Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. Conclusions: The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.Kathryn Hattersley, Kate J Laurie, Jan E Liebelt, Jozef Gecz, Shane R Durkin, Jamie E Craig and Kathryn P Burdo

Nature futures for the urban century : Integrating multiple values into urban management

There is an emerging consensus that the health of the planet depends on the coexistence between rapidly growing cities and the natural world. One strategy for guiding cities towards sustainability is to facilitate a planning process based on positive visions for urban systems among actors and stakeholders. This paper presents the Urban Nature Futures Framework (UNFF), a framework for scenario building for cities that is based on three Nature Futures perspectives: Nature for Nature, Nature for Society, and Nature as Culture. Our framework engages stakeholders with envisioning the three Nature Futures perspectives through four components using participatory methods and quantitative models: identification of the socio-ecological feedbacks in cities, assessment of indirect impacts of cities on biodiversity, development of multi-scale indicators, and development of scenarios. Stakeholders in cities may use this framework to explore different options for integrating nature in its various manifestations within urban areas and to assess how different community preferences result in various cityscapes and distribution of associated benefits from nature among urban dwellers across multiple scales

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Further delineation of Malan syndrome

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only

Gene-specific facial dysmorphism in Axenfeld-Rieger syndrome caused by FOXC1 and PITX2 variants

Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling

Singlet‐Oxygen Generation by Peroxidases and Peroxygenases for Chemoenzymatic Synthesis

Singlet oxygen is a reactive oxygen species undesired in living cells but a rare and valuable reagent in chemical synthesis. We present a fluorescence spectroscopic analysis of the singlet-oxygen formation activity of commercial peroxidases and novel peroxygenases. Singlet-oxygen sensor green (SOSG) is used as fluorogenic singlet oxygen trap. Establishing a kinetic model for the reaction cascade to the fluorescent SOSG endoperoxide permits a kinetic analysis of enzymatic singlet-oxygen formation. All peroxidases and peroxygenases show singlet-oxygen formation. No singlet oxygen activity could be found for any catalase under investigation. Substrate inhibition is observed for all reactive enzymes. The commercial dye-decolorizing peroxidase industrially used for dairy bleaching shows the highest singlet-oxygen activity and the lowest inhibition. This enzyme was immobilized on a textile carrier and successfully applied for a chemical synthesis. Here, ascaridole was synthesized via enzymatically produced singlet oxygen. © 2020 Wiley-VCH Gmb