TY - JOUR A1 - Jansch, Charline A1 - Ziegler, Georg C. A1 - Forero, Andrea A1 - Gredy, Sina A1 - Wäldchen, Sina A1 - Vitale, Maria Rosaria A1 - Svirin, Evgeniy A1 - Zöller, Johanna E. M. A1 - Waider, Jonas A1 - Günther, Katharina A1 - Edenhofer, Frank A1 - Sauer, Markus A1 - Wischmeyer, Erhard A1 - Lesch, Klaus-Peter T1 - Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly JF - Journal of Neural Transmission N2 - Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders. KW - neuropsychiatric disorders KW - human induced pluripotent stem cell (hiPSC) KW - serotonin-specific neurons KW - median and dorsal raphe KW - synapse formation KW - Cadherin-13 (CDH13) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268519 SN - 1435-1463 VL - 128 IS - 2 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Almos, Peter A1 - McNeill, Rhiannon V. A1 - Jansch, Charline A1 - Lesch, Klaus‐Peter T1 - Cellular effects and clinical implications of SLC2A3 copy number variation JF - Journal of Cellular Physiology N2 - SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non‐allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT. KW - copy number variation KW - energy metabolism KW - glucose transporter KW - GLUT3 KW - neurodegeneration KW - neurodevelopment KW - SLC2A3 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218009 VL - 235 IS - 12 SP - 9021 EP - 9036 ER - TY - JOUR A1 - Veniaminova, Ekaterina A1 - Cespuglio, Raymond A1 - Chernukha, Irina A1 - Schmitt-Boehrer, Angelika G. A1 - Morozov, Sergey A1 - Kalueff, Allan V. A1 - Kuznetsova, Oxana A1 - Anthony, Daniel C. A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana T1 - Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity? JF - Frontiers in Neuroscience N2 - Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a “Western diet” (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert\(^{−/−}\): KO), heterozygous (Sert\(^{+/−}\): HET), or wild-type mice (Sert\(^{+/+}\): WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a “rescued” phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert\(^{+/−}\) mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism. KW - Sert-deficient mice KW - Western diet KW - aging KW - glucose tolerance KW - Toll-like receptor 4 (TLR4) KW - serotonin receptors KW - obesity KW - heterosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199813 SN - 1662-453X VL - 14 ER - TY - JOUR A1 - Couch, Yvonne A1 - Trofimov, Alexander A1 - Markova, Natalyia A1 - Nikolenko, Vladimir A1 - Steinbusch, Harry W. A1 - Chekhonin, Vladimir A1 - Schroeter, Careen A1 - Lesch, Klaus-Peter A1 - Anthony, Daniel C. A1 - Strekalova, Tatyana T1 - Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice JF - Journal of Neuroinflammation N2 - Background Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Methods Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. Results When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. Conclusions It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours. KW - SERT KW - Chronic stress KW - LPS KW - Aggressive behaviour KW - S-HT KW - Cytokines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165676 VL - 13 IS - 108 ER - TY - JOUR A1 - Meyer, Neele A1 - Richter, S. Helene A1 - Schreiber, Rebecca S. A1 - Kloke, Vanessa A1 - Kaiser, Sylvia A1 - Lesch, Klaus-Peter A1 - Sachser, Norbert T1 - The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype JF - Frontiers in Behavioral Neuroscience N2 - Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior. KW - adolescence KW - aggressiveness KW - serotonin transporter KW - coping with challenge KW - adversity KW - anxiety-like behavior KW - social experience KW - 5-HTT knockout mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165090 VL - 10 IS - 97 ER - TY - JOUR A1 - Lechermeier, Carina G. A1 - Zimmer, Frederic A1 - Lüffe, Teresa M. A1 - Lesch, Klaus-Peter A1 - Romanos, Marcel A1 - Lillesaar, Christina A1 - Drepper, Carsten T1 - Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system JF - Frontiers in Molecular Neuroscience N2 - The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders. KW - glucose transporter KW - nervous system KW - brain disorders KW - psychiatric disorders KW - brain development KW - GABA KW - GAD1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201797 VL - 12 IS - 199 ER - TY - JOUR A1 - Weidner, Magdalena T. A1 - Lardenoije, Roy A1 - Eijssen, Lars A1 - Mogavero, Floriana A1 - De Groodt, Lilian P. M. T. A1 - Popp, Sandy A1 - Palme, Rupert A1 - Förstner, Konrad U. A1 - Strekalova, Tatyana A1 - Steinbusch, Harry W. M. A1 - Schmitt-Böhrer, Angelika G. A1 - Glennon, Jeffrey C. A1 - Waider, Jonas A1 - van den Hove, Daniel L. A. A1 - Lesch, Klaus-Peter T1 - Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala JF - Frontiers in Neuroscience N2 - Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability. KW - serotonin KW - maternal separation KW - mouse KW - emotional behavior KW - DNA methylation KW - RNA expression Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201340 VL - 13 ER - TY - JOUR A1 - Waider, Jonas A1 - Popp, Sandy A1 - Mlinar, Boris A1 - Montalbano, Alberto A1 - Bonfiglio, Francesco A1 - Aboagye, Benjamin A1 - Thuy, Elisabeth A1 - Kern, Raphael A1 - Thiel, Christopher A1 - Araragi, Naozumi A1 - Svirin, Evgeniy A1 - Schmitt-Böhrer, Angelika G. A1 - Corradetti, Renato A1 - Lowry, Christopher A. A1 - Lesch, Klaus-Peter T1 - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity JF - Frontiers in Neuroscience N2 - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses. KW - tryptophan hydroxylase 2 KW - knockout KW - fear learning KW - extinction KW - long-term potentiation KW - hippocampus KW - immediate-early gene KW - serotonin deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077 SN - 1662-453X VL - 13 IS - 245 ER - TY - JOUR A1 - Waider, J A1 - Popp, S A1 - Lange, MD A1 - Kern, R A1 - Kolter, JF A1 - Kobler, J A1 - Donner, NC A1 - Lowe, KR A1 - Malzbender, JH A1 - Brazell, CJ A1 - Arnold, MR A1 - Aboagye, B A1 - Schmitt-Böhrer, A A1 - Lowry, CA A1 - Pape, HC A1 - Lesch, KP T1 - Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice JF - Translational Psychiatry N2 - Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala. KW - anxiety KW - stress KW - serotonin KW - genetics KW - mice Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170239 VL - 7 IS - e1246 ER - TY - JOUR A1 - Neufang, S. A1 - Akhrif, A. A1 - Herrmann, C.G. A1 - Drepper, C. A1 - Homola, G.A. A1 - Nowak, J. A1 - Waider, J. A1 - Schmitt, A.G. A1 - Lesch, K.-P. A1 - Romanos, M. T1 - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans JF - Translational Psychiatry N2 - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies. KW - Clinical Genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418 IS - 6 ER -