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Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure

Research output: Contribution to journalArticle

Markus Reichold, Enriko D Klootwijk, Joerg Reinders, Edgar A Otto, Mario Milani, Carsten Broeker, Chris Laing, Julia Wiesner, Sulochana Devi, Weibin Zhou, Roland Schmitt, Ines Tegtmeier, Christina Sterner, Hannes Doellerer, Kathrin Renner, Peter J Oefner, Katja Dettmer, Johann M Simbuerger, Ralph Witzgall, Horia C Stanescu & 30 more Simona Dumitriu, Daniela Iancu, Vaksha Patel, Monika Mozere, Mehmet Tekman, Graciana Jaureguiberry, Naomi Issler, Anne Kesselheim, Stephen B Walsh, Daniel P Gale, Alexander J Howie, Joana R Martins, Andrew M Hall, Michael Kasgharian, Kevin O'Brien, Carlos R Ferreira, Paldeep S Atwal, Mahim Jain, Alexander Hammers, Geoffrey Charles-Edwards, Chi-Un Choe, Dirk Isbrandt, Alberto Cebrian-Serrano, Ben Davies, Richard N Sandford, Christopher Pugh, David S Konecki, Sue Povey, Detlef Bockenhauer, Uta Lichter-Konecki

Original languageEnglish
JournalJournal of the American Society of Nephrology : JASN
Early online date13 Apr 2018
Accepted/In press27 Feb 2018
E-pub ahead of print13 Apr 2018
PublishedAug 2018

King's Authors


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. GATM aggregates-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.

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