Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.1.1-1 | Award Amount: 14.69M | Year: 2013
Cancers are genetic disease arising from the accumulation of multiple molecular alterations in affected cells. Large-scale genomic, transcriptomic and proteomic analyses have established comprehensive catalogues of molecules which are altered in their structure and/or abundance in malignant tumors as compared to healthy tissues. Far less developed are concepts and methods to integrate data from different sources and to directly interrogate gene functions on a large scale in order to differentiate driver alterations, which directly contribute to tumor progression, from indolent passenger alterations. As a consequence, examples of successful translation of knowledge generated from omics approaches into novel clinical concepts and applications are scarce. Pancreatic cancer is a prime example of this dilemma. Representing the 4th to 5th most common cause of cancer related deaths, it is a disease with a major socioeconomic impact. Despite enormous advances in the identification of molecular changes associated with the disease, new treatment options have not emerged. Thus, 5-year survival rates remain unchanged at a dismal 6%, the lowest for all solid tumors. Using pancreatic cancer as a model disease, the goal of this integrative project is to develop novel cellular and animal models, as well as novel strategies to generate, analyze and integrate large scale metabolic and transcriptomic data from these models, in order to systematically characterize and validate novel targets for therapeutic intervention. In addition to the general tumor cell population, special consideration will be given to sub-populations of tumor-initiating cells, a.k.a. tumor stem cells. To this end, the consortium comprises i) SMEs with strong focus on technology development, ii) clinical and academic partners with extensive experience in pancreatic cancer molecular biology and management of pancreatic cancer patients, and iii) technology and data analysis experts from academic groups.
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.2.1-4 | Award Amount: 16.45M | Year: 2013
DESIRE will focus on epileptogenic developmental disorders EDD, i.e. early onset epilepsies whose origin is closely related to developmental brain processes. A major cause of EDD are malformations of cortical development (MCD), either macroscopic or subtle. EDD are often manifested as epileptic encephalopathies (EE), i.e. conditions in which epileptic activity itself may contribute to severe cognitive and behavioral impairments. EDD are the most frequent drug-resistant pediatric epilepsies carrying a lifelong perspective of disability and reduced quality of life. Although EDD collectively represent a major medical and socio-economic burden, their molecular diagnosis, pathogenic mechanisms (PM) and rationale treatment are poorly understood. Specific objectives of DESIRE are to advance the state of the art with respect to: (1) the genetic and epigenetic causes and PM of EDD, particularly epileptogenic MCD, to elucidate molecular networks and disrupted protein complexes and search for common bases for these apparently heterogeneous disorders. (2) the diagnostic tools (biomarkers) and protocols through the study of a unique and well-characterized cohort of children to provide standardized diagnosis for patient stratification and research across Europe. (3) treatment of EDD using randomized, multidisciplinary clinical protocols and testing preclinical strategies in experimental models to also address novel preventative strategies. The workplan spans from clinical observation, to whole exome studies, cellular and animal models and basic research, identification of biomarkers and improvement of diagnostic methods, and back to the clinical trials and assessment of innovative, targeted treatment strategies. The consortium partners have an outstanding track record in genetics, basic neurophysiology, neuropathology and clinical research. Specialized expertise will be made available by the SMEs involved to develop novel diagnostic tools for tailored treatment approaches.
Lechner S.,Heinrich Heine University Düsseldorf |
Lechner S.,CeGaT GmbH |
Ferretti L.,University Pierre and Marie Curie |
Ferretti L.,Collège de France |
And 4 more authors.
Molecular Biology and Evolution | Year: 2014
Deciphering the evolutionary processes driving nucleotide variation in multiallelic genes is limited by the number of genetic systems in which such genes occur. The complementary sex determiner (csd) gene in the honey bee Apis mellifera is an informative example for studying allelic diversity and the underlying evolutionary forces in a well-described model of balancing selection. Acting as the primary signal of sex determination, diploid individuals heterozygous for csd develop into females, whereas csd homozygotes are diploid males that have zero fitness. Examining 77 of the functional heterozygous csd allele pairs, we established a combinatorical criteria that provide insights into the minimum number of amino acid differences among those pairs. Given a data set of 244 csd sequences, we show that the total number of csd alleles found in A. mellifera ranges from 53 (locally) to 87 (worldwide), which is much higher than was previously reported (20). Using a coupon-collector model, we extrapolate the presence of in total 116-145 csd alleles worldwide. The hypervariable region (HVR) is of particular importance in determining csd allele specificity, and we provide for this region evidence of high evolutionary rate for length differences exceeding those of microsatellites. The proportion of amino acids driven by positive selection and the rate of nonsynonymous substitutions in the HVR-flanking regions reach values close to 1 but differ with respect to the HVR length. Using a model of csd coalescence, we identified the high originating rate of csd specificities as a major evolutionary force, leading to an origin of a novel csd allele every 400,000 years. The csd polymorphism frequencies in natural populations indicate an excess of new mutations, whereas signs of ancestral transspecies polymorphism can still be detected. This study provides a comprehensive view of the enormous diversity and the evolutionary forces shaping a multiallelic gene. © 2013 The Author.
Docker D.,Klinikum Stuttgart Olgahospital |
Schubach M.,CeGaT GmbH |
Menzel M.,CeGaT GmbH |
Munz M.,Hertie Institute for Clinical Brain Research |
And 5 more authors.
European Journal of Human Genetics | Year: 2014
SATB2 is an evolutionarily highly conserved chromatin remodeling gene located on chromosome 2q33.1. Vertebrate animal models have shown that Satb2 has a crucial role in craniofacial patterning and osteoblast differentiation, as well as in determining the fates of neuronal projections in the developing neocortex. In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID). A single patient carrying a nonsense mutation in SATB2 has been described to date. In this study, we performed trio-exome sequencing in a 3-year-old girl with CP and severely delayed speech development, and her unaffected parents. Previously, the girl had undergone conventional and molecular karyotyping (microarray analysis), as well as targeted analysis for different diseases associated with developmental delay, including Angelman syndrome, Rett syndrome and Fragile X syndrome. No diagnosis could be established. Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene (c.715C>T; p.R239*). The identification of a second patient carrying a de novo nonsense mutation in SATB2 confirms that this gene is essential for normal craniofacial patterning and cognitive development. Based on our data and the literature published so far, we propose a new clinically recognizable syndrome - the SATB2-associated syndrome (SAS). SAS is likely to be underdiagnosed and should be considered in children with ID, severe speech delay, cleft or high-arched palate and abnormal dentition with crowded and irregularly shaped teeth. © 2014 Macmillan Publishers Limited All rights reserved.
Szolek A.,University of Tübingen |
Schubert B.,University of Tübingen |
Mohr C.,University of Tübingen |
Sturm M.,University of Tübingen |
And 2 more authors.
Bioinformatics | Year: 2014
Motivation: The human leukocyte antigen (HLA) gene cluster plays a crucial role in adaptive immunity and is thus relevant in many biomedical applications. While next-generation sequencing data are often available for a patient, deducing the HLA genotype is difficult because of substantial sequence similarity within the cluster and exceptionally high variability of the loci. Established approaches, therefore, rely on specific HLA enrichment and sequencing techniques, coming at an additional cost and extra turnaround time. Result: We present OptiType, a novel HLA genotyping algorithm based on integer linear programming, capable of producing accurate predictions from NGS data not specifically enriched for the HLA cluster. We also present a comprehensive benchmark dataset consisting of RNA, exome and whole-genome sequencing data. OptiType significantly outperformed previously published in silico approaches with an overall accuracy of 97% enabling its use in a broad range of applications. © The Author 2014. Published by Oxford University Press.
Haack T.B.,Helmholtz Center for Environmental Research |
Haack T.B.,TU Munich |
Danhauser K.,Helmholtz Center for Environmental Research |
Danhauser K.,TU Munich |
And 21 more authors.
Nature Genetics | Year: 2010
An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex Iĝ€"defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles. © 2010 Nature America, Inc. All rights reserved.
Kettwig M.,University of Gottingen |
Schubach M.,CeGaT GmbH |
Zimmermann F.A.,Paracelsus Medical University |
Klinge L.,University of Gottingen |
And 5 more authors.
Mitochondrion | Year: 2015
The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5. years he developed hearing loss and severe ataxia and at age 10. years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5. years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent. © 2015.
Chae E.,Max Planck Institute for Developmental Biology |
Bomblies K.,Max Planck Institute for Developmental Biology |
Bomblies K.,Harvard University |
Kim S.-T.,Max Planck Institute for Developmental Biology |
And 19 more authors.
Cell | Year: 2014
Intraspecific genetic incompatibilities prevent the assembly of specific alleles into single genotypes and influence genome- and species-wide patterns of sequence variation. A common incompatibility in plants is hybrid necrosis, characterized by autoimmune responses due to epistatic interactions between natural genetic variants. By systematically testing thousands of F1 hybrids of Arabidopsis thaliana strains, we identified a small number of incompatibility hot spots in the genome, often in regions densely populated by nucleotide-binding domain and leucine-rich repeat (NLR) immune receptor genes. In several cases, these immune receptor loci interact with each other, suggestive of conflict within the immune system. A particularly dangerous locus is a highly variable cluster of NLR genes, DM2, which causes multiple independent incompatibilities with genes that encode a range of biochemical functions, including NLRs. Our findings suggest that deleterious interactions of immune receptors limit the combinations of favorable disease resistance alleles accessible to plant genomes. © 2014 Elsevier Inc.
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 6.00M | Year: 2016
COSYN integrates outstanding European academic and three large Pharma to exploit genomic findings for intellectual disability (ID), autism, and schizophrenia. We capitalise on comorbidity, from clinic to cells and synapses, and have access to large existing samples. We focus on rare genetic variants of strong effect in patients with clinical comorbidity. Our aims are: (1) Understand comorbidity by comparing symptom and syndrome overlap with novel neurobiological criteria; (2) Elucidate mechanisms of comorbidity using neurobiology for the major genomic clue of synaptic dysfunction to unravel the cellular mechanisms of comorbidity; (3) Generate novel neuronal cell models by using advanced technologies to make neurons from carefully selected patients, and use genome editing to create or correct genetic variants. Multiple advanced neuroscience platforms are in place to evaluate an extensive set of molecular and cellular parameters, and to identify alterations in synaptic biology characteristic of ID, autism, and schizophrenia. These cellular models will, with Pharma partners, be up-scaled to provide industry-standard cellular assays for compound screening; (4) Refine diagnostic tools, use novel genomic and cellular features to improve disease classification and discriminate specific patient subtypes; and (5) Case studies in precision medicine: with Pharma partners, identify patients with a genetic change whose consequences can be reproducibly ameliorated in vitro by an approved medication. Recommend to the patient and clinician a double-blinded, N-of-one crossover case study to evaluate the clinical utility of a medication precisely indicated for that person. COSYN is an integrated, state-of-art, bench-to-bedside programme focused on personalised therapeutics. COSYN is a crucial next step in decoding the genetic findings via intensive focus on the clinical and molecular comorbidities of ID, autism, and schizophrenia.
Kohl S.,Forschungsinstitut For Augenheilkunde |
Biskup S.,Olgahospital |
Biskup S.,CeGaT GmbH
Klinische Monatsblatter fur Augenheilkunde | Year: 2013
Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Lebers congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine. © Georg Thieme Verlag KG Stuttgart · New York.