5 results on '"Hänisch B"'
Search Results
2. Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans
- Author
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Matthias Begemann, Regula Steiner, Markus Bergmann, Gergely Karsai, Miriam Elbracht, Thorsten Hornemann, G C Korenke, Cordula Knopp, Florian Kraft, Saranya Suriyanarayanan, Michael Mull, Ingo Kurth, J. M. Schröder, Joachim Weis, Natja Haag, and Hänisch B
- Subjects
0303 health sciences ,Metabolite ,Cellular differentiation ,Disease ,Neurological disorder ,Biology ,medicine.disease ,Sphingolipid ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,Peripheral nervous system ,medicine ,CRISPR ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,Function (biology) ,030304 developmental biology - Abstract
Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) inDEGS1,encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-basedDEGS1knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable.AbbreviationsSLSphingolipidsSPTserine-palmitoyltransferaseCerCeramidesdhCerdihydroceramideS1Psphingosine-1-phosphateSOsphingosineHSANhereditary sensory and autonomic neuropathy
- Published
- 2018
3. Replication of Functional Serotonin Receptor Type 3A and B Variants in Bipolar Affective Disorder: A European Multicenter Study
- Author
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Hammer, C, Cichon, S, Mühleisen, T W, Haenisch, B, Degenhardt, F, Breuer, R, Witt, S H, Strohmaier, J, Oruc, L, Rivas, F, Babadjanova, G, Grigoroiu-Serbanescu, M, Röth, R, Rappold, G, Rietschel, M, Nöthen, M M, Niesler, B, Mattheisen, Manuel, and Hauser, J
- Subjects
association ,bipolar ,BPAD ,HTR3 ,HTR3B ,5-HT3 - Abstract
Serotonin type 3 receptors (\(5-HT_3\)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the \(HTR3A\) and \(HTR3B\) genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802–0.968) for the non-synonymous functional SNP \(HTR3B\) p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of \(HTR3A\) and \(HTR3B\) mRNA in the human brain. \(HTR3A\) and \(HTR3B\) were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired \(5-HT_3\) receptor function in BPAD.
- Published
- 2012
- Full Text
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4. Cerebral chemoarchitecture shares organizational traits with brain structure and function.
- Author
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Hänisch B, Hansen JY, Bernhardt BC, Eickhoff SB, Dukart J, Misic B, and Valk SL
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- Humans, Brain Mapping, Positron-Emission Tomography, Diffusion Magnetic Resonance Imaging, Magnetic Resonance Imaging methods, Brain diagnostic imaging
- Abstract
Chemoarchitecture, the heterogeneous distribution of neurotransmitter transporter and receptor molecules, is a relevant component of structure-function relationships in the human brain. Here, we studied the organization of the receptome, a measure of interareal chemoarchitectural similarity, derived from positron-emission tomography imaging studies of 19 different neurotransmitter transporters and receptors. Nonlinear dimensionality reduction revealed three main spatial gradients of cortical chemoarchitectural similarity - a centro-temporal gradient, an occipito-frontal gradient, and a temporo-occipital gradient. In subcortical nuclei, chemoarchitectural similarity distinguished functional communities and delineated a striato-thalamic axis. Overall, the cortical receptome shared key organizational traits with functional and structural brain anatomy, with node-level correspondence to functional, microstructural, and diffusion MRI-based measures decreasing along a primary-to-transmodal axis. Relative to primary and paralimbic regions, unimodal and heteromodal regions showed higher receptomic diversification, possibly supporting functional flexibility., Competing Interests: BH, JH, BB, SE, JD, BM, SV No competing interests declared, (© 2023, Hänisch et al.)
- Published
- 2023
- Full Text
- View/download PDF
5. DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.
- Author
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Karsai G, Kraft F, Haag N, Korenke GC, Hänisch B, Othman A, Suriyanarayanan S, Steiner R, Knopp C, Mull M, Bergmann M, Schröder JM, Weis J, Elbracht M, Begemann M, Hornemann T, and Kurth I
- Subjects
- Amino Acid Substitution, Cell Line, Female, Humans, Male, Exome Sequencing, Central Nervous System Diseases enzymology, Central Nervous System Diseases genetics, Central Nervous System Diseases pathology, Fatty Acid Desaturases genetics, Fatty Acid Desaturases metabolism, Lipid Metabolism, Inborn Errors enzymology, Lipid Metabolism, Inborn Errors genetics, Lipid Metabolism, Inborn Errors pathology, Mutation, Missense, Sphingosine genetics, Sphingosine metabolism
- Abstract
Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive., Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder., Results: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1., Conclusion: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems., Trial Registration: Not applicable., Funding: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.
- Published
- 2019
- Full Text
- View/download PDF
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