Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD.'' All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.Genetics of disease, diagnosis and treatmen

Chemical and enzymatic synthesis of gene fragments : a laboratory manual/ Edit.: H.G. Gassen

x, p. 249.: ill.; 25 c

L-aspartate oxidase from Escherichia coli. I. Characterization of coenzyme binding and product inhibition

This paper reports the biochemical characterization of the flavoprotein L-aspartate oxidase from Escherichia coli. Modification of a previously published procedure allowed overexpression of the holoenzyme in an unproteolysed form. L-Aspartate oxidase is a monomer of 60 kDa containing 1 mol of noncovalently bound FAD/mol protein. A polarographic and two spectrophotometric coupled assays have been set up to monitor the enzymatic activity continuously. L-Aspartate oxidase was subjected to product inhibition since iminoaspartate, which results from the oxidation of L-aspartate, binds to the enzyme with a dissociation constant (Kd) equal to 1.4 microM. The enzyme binds FAD by a simple second-order process with Kd 0.67 microM. Site-directed mutagenesis of the residues E43, G44, S45, F47 and Y48 located in the putative binding site of the isoallossazinic portion of FAD reduces the affinity for the coenzyme

Biotechnologie im Rhein/Main-Gebiet Eine faszinierende Chance. Schlussbericht

In a leading region of economic and scientific activities the working group of BioRegio Rhein-Main is proposing a concept to strengthen the commercial application of biotechnological knowledge in order to accelerate the development of the region to the European centre of biotechnology. A network is build up, which makes it possible to connect enterprises and scientists working on biotechnological and related topics. Furthermore measures and models of organization are described, which will be able to improve the regional conditions for biotechnology. The crucial points of the proposed concept are: -Improvement of the regional conditions by connecting the available resources through a network in order to increase the competitiveness of existing enterprises. - Support of biotech-start-ups an active use of links and interfaces between universities and enterprises. Crucial for the success of the proposed measures will be the creation of a biotechnological information and advisory service offering the integration of technological transfer projects with marketing considerations and financial opportunities. (orig.)SIGLEAvailable from TIB Hannover: F97B1429+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman