Steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) are leading causes of end-stage renal failure in children, adolescents, and adults. Constant progress in sequencing technologies allowed for the evolving identification of causative genes, both in familial and sporadic SRNS cases. While several SRNS genes could be identified in children, the genetic basis of SRNS/FSGS in adolescents and adults is much less clear. To tackle the lack of understanding of the disease in these subgroups we aim to use state-of-the-art sequencing approaches at various levels of biological hierarchy:
1) To improve detection of genomic causes for the disease we combine short-read based high capacity next-generation sequencing with new computational and advanced technologies for structural variation analysis. Combined with deep clinical phenotyping we will explore patient stratification in a more data-driven approach.
2) We aim to characterize cell-free DNA (cfDNA), released by injured tissues, to detect tissue damage in a minimally invasive way and to establish key tissues that contribute or are equally affected by the disease. We hope to establish cfDNA as an early biomarker to monitor the state and progression of injury in MCD/FSGS/FSGS-R patients in real-time.
3) Employ reverse cartography approaches on single-cell transcriptional data to better understand tissue architecture and cellular neighborhood of key cells, such as podocytes. Here we aim to combine imaging techniques, direct RNA labeling via RNAscope, and single-cell RNA sequencing to develop spatial reconstruction approaches that can accurately represent these tissues and analyze how cellular neighborhoods are impacted by the disease.
In summary, we aim to significantly improve the detection of genetic causes or predispositions for FSGS on multiple levels and to enhance our understanding of the pathomechanisms leading to disease development and progression up to the level of single cells. This will ultimately contribute to discoveries able to drive relevant changes in clinical practice by precision diagnostics and open the way to the establishment of individualized therapies.
PROJECT RELATED PUBLICATIONS
Weng, P.L., Majmundar, A.J., Khan, K., Lim, T.Y., Shril, S., Jin, G., Musgrove, J., Wang, M., Ahram, D.F., Aggarwal, V.S., Bier, L.E., Heinzen, E.L., Onuchic-Whitford, A.C., Mann, N., Buerger, F., Schneider, R., Deutsch, K., Kitzler, T.M., Klambt, V., Kolb, A., Mao, Y., Moufawad El Achkar, C., Mitrotti, A., Martino, J., Beck, B.B., Altmuller, J., Benz, M.R., Yano, S., Mikati, M.A., Gunduz, T., Cope, H., Shashi, V., Undiagnosed Diseases, N., Trachtman, H., Bodria, M., Caridi, G., Pisani, I., Fiaccadori, E., AbuMaziad, A.S., Martinez-Agosto, J.A., Yadin, O., Zuckerman, J., Kim, A., Center, U.C.G., John-Kroegel, U., Tyndall, A.V., Parboosingh, J.S., Innes, A.M., Bierzynska, A., Koziell, A.B., Muorah, M., Saleem, M.A., Hoefele, J., Riedhammer, K.M., Gharavi, A.G., Jobanputra, V., Pierce-Hoffman, E., Seaby, E.G., O'Donnell-Luria, A., Rehm, H.L., Mane, S., D'Agati, V.D., Pollak, M.R., Ghiggeri, G.M., Lifton, R.P., Goldstein, D.B., Davis, E.E., Hildebrandt, F., and Sanna-Cherchi, S. (2021) De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet, 108(2): 357-367.
Schlingmann, K.P., Jouret, F., Shen, K., Nigam, A., Arjona, F.J., Dafinger, C., Houillier, P., Jones, D.P., Kleineruschkamp, F., Oh, J., Godefroid, N., Eltan, M., Guran, T., Burtey, S., Parotte, M.C., Konig, J., Braun, A., Bos, C., Ibars Serra, M., Rehmann, H., Zwartkruis, F.J.T., Renkema, K.Y., Klingel, K., Schulze-Bahr, E., Schermer, B., Bergmann, C., Altmuller, J., Thiele, H., Beck, B.B., Dahan, K., Sabatini, D., Liebau, M.C., Vargas-Poussou, R., Knoers, N., Konrad, M., and de Baaij, J.H.F. (2021) mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy. J Am Soc Nephrol, 32(11): 2885-2899.
Reusch, B., Bartram, M.P., Dafinger, C., Palacio-Escat, N., Wenzel, A., Fenton, R.A., Saez-Rodriguez, J., Schermer, B., Benzing, T., Altmuller, J., Beck, B.B., and Rinschen, M.M. (2021) MAGED2 controls vasopressin-induced aquaporin-2 expression in collecting duct cells. J Proteomics, 252: 104424.
Fabretti, F., Tschernoster, N., Erger, F., Hedergott, A., Buescher, A.K., Dafinger, C., Reusch, B., Kontges, V.K., Kohl, S., Bartram, M.P., Weber, L.T., Thiele, H., Altmueller, J., Schermer, B., Beck, B.B., and Habbig, S. (2021) Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling. Kidney Int Rep, 6(5): 1368-1378.
Erger, F., Norling, D., Borchert, D., Leenen, E., Habbig, S., Wiesener, M.S., Bartram, M.P., Wenzel, A., Becker, C., Toliat, M.R., Nurnberg, P., Beck, B.B., and Altmuller, J. (2020) cfNOMe - A single assay for comprehensive epigenetic analyses of cell-free DNA. Genome Med, 12(1): 54.
