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14 results on '"Harrer, Philip"'

1. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

Author

Schormair, Barbara, Zhao, Chen, Bell, Steven, Didriksen, Maria, Nawaz, Muhammad S., Schandra, Nathalie, Stefani, Ambra, Högl, Birgit, Dauvilliers, Yves, Bachmann, Cornelius G., Kemlink, David, Sonka, Karel, Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H., Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M., Polo, Olli, Fietze, Ingo, Ross, Owen A., Wszolek, Zbigniew K., Ibrahim, Abubaker, Bergmann, Melanie, Kittke, Volker, Harrer, Philip, Dowsett, Joseph, Chenini, Sofiene, Ostrowski, Sisse Rye, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole B., Topholm Bruun, Mie, Nielsen, Kaspar R., Butterworth, Adam S., Soranzo, Nicole, Ouwehand, Willem H., Roberts, David J., Danesh, John, Burchell, Brendan, Furlotte, Nicholas A., Nandakumar, Priyanka, Earley, Christopher J., Ondo, William G., Xiong, Lan, Desautels, Alex, Perola, Markus, Vodicka, Pavel, Dina, Christian, Stoll, Monika, Franke, Andre, Lieb, Wolfgang, Stewart, Alexandre F. R., Shah, Svati H., Gieger, Christian, Peters, Annette, Rye, David B., Rouleau, Guy A., Berger, Klaus, Stefansson, Hreinn, Ullum, Henrik, Stefansson, Kari, Hinds, David A., Di Angelantonio, Emanuele, Oexle, Konrad, and Winkelmann, Juliane

Published
2024
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3. Molecular analysis of movement disorders - genomic and epigenomic approaches

Author

Winkelmann, Juliane (Prof. Dr.), Oexle, Konrad (Prof. Dr.);Meitinger, Thomas (Prof. Dr.);Klein, Christine (Prof. Dr.), Harrer, Philip Wolfgang, Winkelmann, Juliane (Prof. Dr.), Oexle, Konrad (Prof. Dr.);Meitinger, Thomas (Prof. Dr.);Klein, Christine (Prof. Dr.), and Harrer, Philip Wolfgang

Abstract

Movement disorders include monogenic modes of inheritance due to rare variants of large effect size and polygenic forms involving many loci with mild effects. We identified variants in NUP54 and EIF4A2, recognizing two novel monogenic forms of dystonia, and provided evidence for mechanistic changes at the nuclear envelope and translational regulation by targeted protein analyses. For the polygenic disorder RLS we performed EWAS and epigenetic age estimations supporting the notion of altered neurodevelopment but not degeneration and derived a reliable methylation risk score., Bewegungsstörungen umfassen monogene, auf seltenen Varianten mit großer Effektstärke, und polygene, auf vielen Loci mit geringen Effekten beruhende Formen. Wir identifizierten Varianten in NUP54 und EIF4A2, verknüpft mit zwei neuen monogenen Dystonien, und zeigten durch Proteinanalysen Veränderungen an Kernhülle und Translationsregulation auf. Für das polygene RLS führten wir EWAS und epigenetische Altersschätzungen durch, die auf eine veränderte neuronale Entwicklung, nicht aber auf eine Neurodegeneration hindeuteten, und leiteten einen Methylierungsrisikoscore ab.

Published
2024

4. Epigenetic Association Analyses and Risk Prediction of RLS

Author

Harrer, Philip, primary, Mirza‐Schreiber, Nazanin, additional, Mandel, Vanessa, additional, Roeber, Sigrun, additional, Stefani, Ambra, additional, Naher, Shamsun, additional, Wagner, Matias, additional, Gieger, Christian, additional, Waldenberger, Melanie, additional, Peters, Annette, additional, Högl, Birgit, additional, Herms, Jochen, additional, Schormair, Barbara, additional, Zhao, Chen, additional, Winkelmann, Juliane, additional, and Oexle, Konrad, additional

Published
2023
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5. Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction.

Author

Harrer, Philip, Škorvánek, Matej, Kittke, Volker, Dzinovic, Ivana, Borngräber, Friederike, Thomsen, Mirja, Mandel, Vanessa, Svorenova, Tatiana, Ostrozovicova, Miriam, Kulcsarova, Kristina, Berutti, Riccardo, Busch, Hauke, Ott, Fabian, Kopajtich, Robert, Prokisch, Holger, Kumar, Kishore R., Mencacci, Niccolo E., Kurian, Manju A., Di Fonzo, Alessio, and Boesch, Sylvia

Abstract

Background: Protein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions. Methods: We undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts. Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees. Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2023
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6. Recessive NUP54 Variants Underlie Early‐Onset Dystonia with Striatal Lesions

Author

Harrer, Philip, primary, Schalk, Audrey, additional, Shimura, Masaru, additional, Baer, Sarah, additional, Calmels, Nadège, additional, Spitz, Marie Aude, additional, Warde, Marie‐Thérèse Abi, additional, Schaefer, Elise, additional, Kittke, Volker M.Sc, additional, Dincer, Yasemin, additional, Wagner, Matias, additional, Dzinovic, Ivana, additional, Berutti, Riccardo, additional, Sato, Tatsuharu, additional, Shirakawa, Toshihiko, additional, Okazaki, Yasushi, additional, Murayama, Kei, additional, Oexle, Konrad, additional, Prokisch, Holger, additional, Mall, Volker, additional, Melčák, Ivo, additional, Winkelmann, Juliane, additional, and Zech, Michael, additional

Published
2022
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9. Recessive NUP54 Variants Underlie Early‐Onset Dystonia with Striatal Lesions.

Author

Harrer, Philip, Schalk, Audrey, Shimura, Masaru, Baer, Sarah, Calmels, Nadège, Spitz, Marie Aude, Warde, Marie‐Thérèse Abi, Schaefer, Elise, Kittke, Volker M.Sc, Dincer, Yasemin, Wagner, Matias, Dzinovic, Ivana, Berutti, Riccardo, Sato, Tatsuharu, Shirakawa, Toshihiko, Okazaki, Yasushi, Murayama, Kei, Oexle, Konrad, Prokisch, Holger, and Mall, Volker

Subjects
*DYSTONIA, *DEGLUTITION disorders, *PHENOTYPES, *SYNDROMES, *ARGUMENT
Abstract

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear‐pore complex (NPC) gene NUP62, involved in nucleo‐cytoplasmic trafficking. By querying sequencing‐datasets of patients with dystonia and/or Leigh(‐like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C‐terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62‐related disease, including early‐onset dystonia with dysphagia, choreoathetosis, and T2‐hyperintense lesions in striatum. In silico and protein‐biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component‐associated dystonic conditions with localized basal‐ganglia abnormalities. ANN NEUROL 2023;93:330–335 [ABSTRACT FROM AUTHOR]

Published
2023
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10. Erratum : De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders (The American Journal of Human Genetics (2019) 104(1) (139–156), (S0002929718304531) (10.1016/j.ajhg.2018.12.002))

Author

Reynhout, Sara, Jansen, Sandra, Haesen, Dorien, van Belle, Siska, de Munnik, Sonja A., Bongers, Ernie M.H.F., Schieving, Jolanda H., Marcelis, Carlo, Amiel, Jeanne, Rio, Marlène, Mclaughlin, Heather, Ladda, Roger, Sell, Susan, Kriek, Marjolein, Peeters-Scholte, Cacha M.P.C.D., Terhal, Paulien A., van Gassen, Koen L., Verbeek, Nienke, Henry, Sonja, Schwoerer, Jessica Scott, Malik, Saleem, Revencu, Nicole, Ferreira, Carlos R., Macnamara, Ellen, Braakman, Hilde M.H., Brimble, Elise, Ruzhnikov, Maura R.Z., Wagner, Matias, Harrer, Philip, Wieczorek, Dagmar, Kuechler, Alma, Tziperman, Barak, Barel, Ortal, de Vries, Bert B.A., Gordon, Christopher T., Janssens, Veerle, and Vissers, Lisenka E.L.M.

Subjects
Genetics, Genetics(clinical)
Abstract

(The American Journal of Human Genetics 104, 139–156; January 3, 2019) In the original version of this article published on December 27, 2018, Maura R.Z. Ruzhnikov's surname was unfortunately misspelled. It appears correctly here and online. The authors apologize for the error.

Published
2019

11. De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

Author

Reynhout, Sara, Jansen, Sandra, Haesen, Dorien, van Belle, Siska, de Munnik, Sonja A., Bongers, Ernie M.H.F., Schieving, Jolanda H., Marcelis, Carlo, Amiel, Jeanne, Rio, Marlène, Mclaughlin, Heather, Ladda, Roger, Sell, Susan, Kriek, Marjolein, Peeters-Scholte, Cacha M.P.C.D., Terhal, Paulien A., van Gassen, Koen L., Verbeek, Nienke, Henry, Sonja, Scott Schwoerer, Jessica, Malik, Saleem, Revencu, Nicole, Ferreira, Carlos R., Macnamara, Ellen, Braakman, Hilde M.H., Brimble, Elise, Ruznikov, Maura R.Z., Wagner, Matias, Harrer, Philip, Wieczorek, Dagmar, Kuechler, Alma, Tziperman, Barak, Barel, Ortal, de Vries, Bert B.A., Gordon, Christopher T., Janssens, Veerle, Vissers, Lisenka E.L.M., Reynhout, Sara, Jansen, Sandra, Haesen, Dorien, van Belle, Siska, de Munnik, Sonja A., Bongers, Ernie M.H.F., Schieving, Jolanda H., Marcelis, Carlo, Amiel, Jeanne, Rio, Marlène, Mclaughlin, Heather, Ladda, Roger, Sell, Susan, Kriek, Marjolein, Peeters-Scholte, Cacha M.P.C.D., Terhal, Paulien A., van Gassen, Koen L., Verbeek, Nienke, Henry, Sonja, Scott Schwoerer, Jessica, Malik, Saleem, Revencu, Nicole, Ferreira, Carlos R., Macnamara, Ellen, Braakman, Hilde M.H., Brimble, Elise, Ruznikov, Maura R.Z., Wagner, Matias, Harrer, Philip, Wieczorek, Dagmar, Kuechler, Alma, Tziperman, Barak, Barel, Ortal, de Vries, Bert B.A., Gordon, Christopher T., Janssens, Veerle, and Vissers, Lisenka E.L.M.

Published
2019

12. PRDM12 Is Required for Initiation of the Nociceptive Neuron Lineage during Neurogenesis

Author

Bartesaghi, Luca, primary, Wang, Yiqiao, additional, Fontanet, Paula, additional, Wanderoy, Simone, additional, Berger, Finja, additional, Wu, Haohao, additional, Akkuratova, Natalia, additional, Bouçanova, Filipa, additional, Médard, Jean-Jacques, additional, Petitpré, Charles, additional, Landy, Mark A., additional, Zhang, Ming-Dong, additional, Harrer, Philip, additional, Stendel, Claudia, additional, Stucka, Rolf, additional, Dusl, Marina, additional, Kastriti, Maria Eleni, additional, Croci, Laura, additional, Lai, Helen C., additional, Consalez, Gian Giacomo, additional, Pattyn, Alexandre, additional, Ernfors, Patrik, additional, Senderek, Jan, additional, Adameyko, Igor, additional, Lallemend, Francois, additional, Hadjab, Saida, additional, and Chrast, Roman, additional

Published
2019
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13. De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

Author

Reynhout, Sara, primary, Jansen, Sandra, additional, Haesen, Dorien, additional, van Belle, Siska, additional, de Munnik, Sonja A., additional, Bongers, Ernie M.H.F., additional, Schieving, Jolanda H., additional, Marcelis, Carlo, additional, Amiel, Jeanne, additional, Rio, Marlène, additional, Mclaughlin, Heather, additional, Ladda, Roger, additional, Sell, Susan, additional, Kriek, Marjolein, additional, Peeters-Scholte, Cacha M.P.C.D., additional, Terhal, Paulien A., additional, van Gassen, Koen L., additional, Verbeek, Nienke, additional, Henry, Sonja, additional, Schwoerer, Jessica Scott, additional, Malik, Saleem, additional, Revencu, Nicole, additional, Ferreira, Carlos R., additional, Macnamara, Ellen, additional, Braakman, Hilde M.H., additional, Brimble, Elise, additional, Ruzhnikov, Maura R.Z., additional, Wagner, Matias, additional, Harrer, Philip, additional, Wieczorek, Dagmar, additional, Kuechler, Alma, additional, Tziperman, Barak, additional, Barel, Ortal, additional, de Vries, Bert B.A., additional, Gordon, Christopher T., additional, Janssens, Veerle, additional, and Vissers, Lisenka E.L.M., additional

Published
2019
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14. PRDM12 Is Required for Initiation of the Nociceptive Neuron Lineage during Neurogenesis

Author

Ming-Dong Zhang, Helen C. Lai, Francois Lallemend, Roman Chrast, Igor Adameyko, Jan Senderek, Marina Dusl, Luca Bartesaghi, Philip Harrer, Paula Fontanet, Claudia Stendel, Charles Petitpré, Alexandre Pattyn, Haohao Wu, Filipa Bouçanova, Maria Eleni Kastriti, Jean-Jacques Médard, Finja Berger, Mark A. Landy, Yiqiao Wang, Patrik Ernfors, Rolf Stucka, Natalia Akkuratova, Saida Hadjab, Laura Croci, Simone Wanderoy, G. Giacomo Consalez, Bartesaghi, Luca, Wang, Yiqiao, Fontanet, Paula, Wanderoy, Simone, Berger, Finja, Wu, Haohao, Akkuratova, Natalia, Bouçanova, Filipa, Médard, Jean-Jacque, Petitpré, Charle, Landy, Mark A., Zhang, Ming-Dong, Harrer, Philip, Stendel, Claudia, Stucka, Rolf, Dusl, Marina, Eleni Kastriti, Maria, Croci, Laura, Lai, Helen C., Consalez, GIANGIACOMO GERMANO, Pattyn, Alexandre, Ernfors, Patrik, Senderek, Jan, Adameyko, Igor, Lallemend, Francoi, Hadjab, Saida, and Chrast, Roman

Subjects
0301 basic medicine, Male, Nociception, Lineage (genetic), Neurogenesis, Nerve Tissue Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Cell Lineage, Progenitor cell, Transcription factor, lcsh:QH301-705.5, Neurons, Gene Expression Profiling, Neural crest, Nociceptors, Immunohistochemistry, 030104 developmental biology, medicine.anatomical_structure, nervous system, lcsh:Biology (General), NEUROD1, ISL1, Female, Neuron, Carrier Proteins, Neuroscience, Chickens, 030217 neurology & neurosurgery, Transcription Factors
Abstract

SUMMARY The sensation of pain is essential for the preservation of the functional integrity of the body. However, the key molecular regulators necessary for the initiation of the development of pain-sensing neurons have remained largely unknown. Here, we report that, in mice, inactivation of the transcriptional regulator PRDM12, which is essential for pain perception in humans, results in a complete absence of the nociceptive lineage, while proprioceptive and touch-sensitive neurons remain. Mechanistically, our data reveal that PRDM12 is required for initiation of neurogenesis and activation of a cascade of downstream pro-neuronal transcription factors, including NEUROD1, BRN3A, and ISL1, in the nociceptive lineage while it represses alternative fates other than nociceptors in progenitor cells. Our results thus demonstrate that PRDM12 is necessary for the generation of the entire lineage of pain-initiating neurons., Graphical Abstract, In Brief The sensation of pain, temperature, and itch by neurons of the nociceptive lineage is essential for animal survival. Bartesaghi et al. report that the transcriptional regulator PRDM12 is indispensable in neural crest cells (NCCs) for the initiation of the sensory neuronal differentiation program that generates the entire nociceptive lineage.

Published
2019
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