Reichold, Markus and Klootwijk, Enriko D. and Reinders, Joerg and Otto, Edgar A. and Milani, Mario and Broeker, Carsten and Laing, Chris and Wiesner, Julia and Devi, Sulochana and Zhou, Weibin and Schmitt, Roland and Tegtmeier, Ines and Sterner, Christina and Doellerer, Hannes and Renner, Kathrin and Oefner, Peter J. and Dettmer, Katja and Simbuerger, Johann M. and Witzgall, Ralph and Stanescu, Horia C. and Dumitriu, Simona and Iancu, Daniela and Patel, Vaksha and Mozere, Monika and Tekman, Mehmet and Jaureguiberry, Graciana and Issler, Naomi and Kesselheim, Anne and Walsh, Stephen B. and Gale, Daniel P. and Howie, Alexander J. and Martins, Joana R. and Hall, Andrew M. and Kasgharian, Michael and O'Brien, Kevin and Ferreira, Carlos R. and Atwal, Paldeep S. and Jain, Mahim and Hammers, Alexander and Charles-Edwards, Geoffrey and Choe, Chi-Un and Isbrandt, Dirk and Cebrian-Serrano, Alberto and Davies, Ben and Sandford, Richard N. and Pugh, Christopher and Konecki, David S. and Povey, Sue and Bockenhauer, Detlef and Lichter-Konecki, Uta and Gahl, William A. and Unwin, Robert J. and Warth, Richard and Kleta, Robert (2018) Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 29 (7). pp. 1849-1858. ISSN 1046-6673, 1533-3450
Full text not available from this repository. (Request a copy)Abstract
Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATMaggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUBULAR ABSORPTION DEFECT; L-ARGININE; HYPOPHOSPHATEMIC OSTEOMALACIA; CREATINE BIOSYNTHESIS; NLRP3 INFLAMMASOMES; NALP3 INFLAMMASOME; AMINO-ACIDS; ADULT ONSET; FAMILY; FIBROSIS; |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Richard Warth Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie > Prof. Dr. Ralph Witzgall |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Mar 2020 08:07 |
| Last Modified: | 09 Mar 2020 08:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14285 |
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