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256 results on '"Neuen-Jacob E"'

3. De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

Author

Reijnders, M.R.F., Seibt, A., Brugger, M., Lamers, I.J.C., Ott, T., Klaas, O., Horváth, J., Rose, A.M.S., Craghill, I.M., Brunet, T., Graf, E., Mayerhanser, K., Hellebrekers, D., Pauck, D., Neuen-Jacob, E., Rodenburg, R.J.T., Wieczorek, D., Klee, D., Mayatepek, E., Driessen, G., Bindermann, R., Averdunk, L., Lohmeier, K., Sinnema, M., Stegmann, A.P.A., Roepman, R., Poulter, J.A., Distelmaier, F., Reijnders, M.R.F., Seibt, A., Brugger, M., Lamers, I.J.C., Ott, T., Klaas, O., Horváth, J., Rose, A.M.S., Craghill, I.M., Brunet, T., Graf, E., Mayerhanser, K., Hellebrekers, D., Pauck, D., Neuen-Jacob, E., Rodenburg, R.J.T., Wieczorek, D., Klee, D., Mayatepek, E., Driessen, G., Bindermann, R., Averdunk, L., Lohmeier, K., Sinnema, M., Stegmann, A.P.A., Roepman, R., Poulter, J.A., and Distelmaier, F.

Abstract

01 juli 2023, Contains fulltext : 294778.pdf (Publisher’s version ) (Open Access), PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. METHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. RESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model. CONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.

Published
2023

27. Therapy-resistant polymyositis - is the diagnosis correct?

Author

Ceccon, G., Lehmann, H. C., Neuen-Jacob, E., Meng, G., Fink, G. R., Wunderlich, G., Ceccon, G., Lehmann, H. C., Neuen-Jacob, E., Meng, G., Fink, G. R., and Wunderlich, G.

Abstract

We report the case of a 32-year-old woman with severely elevated serum creatine kinase (CK; 80,000 U/l) and progressive proximal pareses. As muscular biopsy showed inflammatory infiltrates, polymyositis was suspected and immunosuppressive treatment was initiated. However, clinical improvement could not be achieved. Gene sequencing of the DYSF-gene showed a previously unreported homozygous mutation. In summary, elevated serum CK and inflammatory infiltrates in the muscle biopsy are not specific for polymyositis, but may also occur in degenerative diseases (muscular dystrophy), such as dysferlinopathy.

Published
2017

45. A.P.3

Author

Semmler, A.L., primary, Sacconi, S., additional, Bach, J.E., additional, Liebe, C., additional, Bürmann, J., additional, Kley, R.A., additional, Ferbert, A., additional, Anderheiden, R., additional, Van den Bergh, P., additional, Martin, J.J., additional, Jonghe, P. De, additional, Neuen-Jacob, E., additional, Müller, O., additional, Deschauer, M., additional, Bergmann, M., additional, Schröder, J.M., additional, Vorgerd, M., additional, Schulz, J.B., additional, Weis, J., additional, Kress, W., additional, and Claeys, K.G., additional

Published
2014
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