Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure
| Autor: | Mahim Jain, Daniela Iancu, Joana Raquel Martins, Robert J. Unwin, Kathrin Renner, Naomi Issler, Chi-Un Choe, Hannes Doellerer, Ralph Witzgall, Stephen B. Walsh, Sulochana Devi, Monika Mozere, Robert Kleta, Johann M.B Simbuerger, Kevin O'Brien, Anne Kesselheim, Markus Reichold, Paldeep S. Atwal, Michael Kasgharian, Uta Lichter-Konecki, William A. Gahl, Carlos Ferreira, Julia Wiesner, Vaksha Patel, Horia Stanescu, Peter J. Oefner, Graciana Jaureguiberry, Christopher W. Pugh, Mario Milani, Joerg Reinders, Christina Sterner, Detlef Bockenhauer, Sue Povey, Simona Dumitriu, Chris Laing, Ben Davies, Carsten Broeker, David S. Konecki, Roland Schmitt, Alexander Hammers, Richard Sandford, Enriko Klootwijk, Dirk Isbrandt, Richard Warth, Daniel P. Gale, Andrew M. Hall, Alberto Cebrian-Serrano, Alexander J. Howie, Weibin Zhou, Geoffrey Charles-Edwards, Ines Tegtmeier, Edgar A. Otto, Mehmet Tekman, Katja Dettmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
complications [Fanconi Syndrome]
Male 0301 basic medicine Nephrology metabolism [Amidinotransferases] Amidinotransferases metabolism [Kidney Failure Chronic] Inflammasomes Molecular Conformation 030232 urology & nephrology Mitochondrion pathology [Mitochondria] Mice chemistry.chemical_compound pathology [Fanconi Syndrome] 0302 clinical medicine Missense mutation metabolism [Reactive Oxygen Species] Mice Knockout Kidney metabolism [Fanconi Syndrome] Genetic disorder General Medicine etiology [Kidney Failure Chronic] Mitochondria Pedigree Editorial medicine.anatomical_structure Knockout mouse genetics [Amidinotransferases] Female Heterozygote medicine.medical_specialty Mutation Missense Biology Creatine genetics [Kidney Failure Chronic] Young Adult 03 medical and health sciences genetic diseases Tubulopathy Internal medicine genetics [Fanconi Syndrome] glycine amidinotransferase medicine Animals Humans Computer Simulation ddc:610 Aged Infant Sequence Analysis DNA Fanconi Syndrome metabolism [Mitochondria] medicine.disease 030104 developmental biology chemistry Mutation Cancer research Kidney Failure Chronic pathology [Kidney Failure Chronic] Reactive Oxygen Species metabolism [Inflammasomes] |
| Zdroj: | Journal of the American Society of Nephrology 29(7), 1849-1858 (2018). doi:10.1681/ASN.2017111179 Journal of the American Society of Nephrology 29 (2018): 1849–1858. doi:10.1681/ASN.2017111179 info:cnr-pdr/source/autori:Reichold M, Klootwijk ED, Reinders J, Otto EA, Milani M, Broeker C, Laing C, Wiesner J, Devi S, Zhou W, Schmitt R, Tegtmeier I, Sterner C, Doellerer H, Renner K, Oefner PJ, Dettmer K, Simbuerger JM, Witzgall R, Stanescu HC, Dumitriu S, Iancu D, Patel V, Mozere M, Tekman M, Jaureguiberry G, Issler N, Kesselheim A, Walsh SB, Gale DP, Howie AJ, Martins JR, Hall AM, Kasgharian M, O'Brien K, Ferreira CR, Atwal PS, Jain M, Hammers A, Charles-Edwards G, Choe CU, Isbrandt D, Cebrian-Serrano A, Davies B, Sandford RN, Pugh C, Konecki DS, Povey S, Bockenhauer D, Lichter-Konecki U, Gahl WA, Unwin RJ, Warth R, Kleta R/titolo:Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure/doi:10.1681%2FASN.2017111179/rivista:Journal of the American Society of Nephrology/anno:2018/pagina_da:1849/pagina_a:1858/intervallo_pagine:1849–1858/volume:29 |
| DOI: | 10.1681/asn.2017111179 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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