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

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

In: J AM SOC NEPHROL, Vol. 29, No. 7, 07.2018, p. 1849-1858.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, C-U, 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 2018, 'Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure', J AM SOC NEPHROL, vol. 29, no. 7, pp. 1849-1858. https://doi.org/10.1681/ASN.2017111179

APA

Reichold, M., Klootwijk, E. D., Reinders, J., Otto, E. A., Milani, M., Broeker, C., Laing, C., Wiesner, J., Devi, S., Zhou, W., Schmitt, R., Tegtmeier, I., Sterner, C., Doellerer, H., Renner, K., Oefner, P. J., Dettmer, K., Simbuerger, J. M., Witzgall, R., ... Kleta, R. (2018). Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. J AM SOC NEPHROL, 29(7), 1849-1858. https://doi.org/10.1681/ASN.2017111179

Vancouver

Reichold M, Klootwijk ED, Reinders J, Otto EA, Milani M, Broeker C et al. Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. J AM SOC NEPHROL. 2018 Jul;29(7):1849-1858. https://doi.org/10.1681/ASN.2017111179

Bibtex

@article{e507e63f493d41f89db879b797204649,
title = "Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure",
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. 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.",
keywords = "Journal Article",
author = "Markus Reichold and Klootwijk, {Enriko D} and Joerg Reinders and Otto, {Edgar A} and Mario Milani and Carsten Broeker and Chris Laing and Julia Wiesner and Sulochana Devi and Weibin Zhou and Roland Schmitt and Ines Tegtmeier and Christina Sterner and Hannes Doellerer and Kathrin Renner and Oefner, {Peter J} and Katja Dettmer and Simbuerger, {Johann M} and Ralph Witzgall and Stanescu, {Horia C} and Simona Dumitriu and Daniela Iancu and Vaksha Patel and Monika Mozere and Mehmet Tekman and Graciana Jaureguiberry and Naomi Issler and Anne Kesselheim and Walsh, {Stephen B} and Gale, {Daniel P} and Howie, {Alexander J} and Martins, {Joana R} and Hall, {Andrew M} and Michael Kasgharian and Kevin O'Brien and Ferreira, {Carlos R} and Atwal, {Paldeep S} and Mahim Jain and Alexander Hammers and Geoffrey Charles-Edwards and Chi-Un Choe and Dirk Isbrandt and Alberto Cebrian-Serrano and Ben Davies and Sandford, {Richard N} and Christopher Pugh and Konecki, {David S} and Sue Povey and Detlef Bockenhauer and Uta Lichter-Konecki and Gahl, {William A} and Unwin, {Robert J} and Richard Warth and Robert Kleta",
note = "Copyright {\textcopyright} 2018 by the American Society of Nephrology.",
year = "2018",
month = jul,
doi = "10.1681/ASN.2017111179",
language = "English",
volume = "29",
pages = "1849--1858",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "7",

}

RIS

TY - JOUR

T1 - Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure

AU - Reichold, Markus

AU - Klootwijk, Enriko D

AU - Reinders, Joerg

AU - Otto, Edgar A

AU - Milani, Mario

AU - Broeker, Carsten

AU - Laing, Chris

AU - Wiesner, Julia

AU - Devi, Sulochana

AU - Zhou, Weibin

AU - Schmitt, Roland

AU - Tegtmeier, Ines

AU - Sterner, Christina

AU - Doellerer, Hannes

AU - Renner, Kathrin

AU - Oefner, Peter J

AU - Dettmer, Katja

AU - Simbuerger, Johann M

AU - Witzgall, Ralph

AU - Stanescu, Horia C

AU - Dumitriu, Simona

AU - Iancu, Daniela

AU - Patel, Vaksha

AU - Mozere, Monika

AU - Tekman, Mehmet

AU - Jaureguiberry, Graciana

AU - Issler, Naomi

AU - Kesselheim, Anne

AU - Walsh, Stephen B

AU - Gale, Daniel P

AU - Howie, Alexander J

AU - Martins, Joana R

AU - Hall, Andrew M

AU - Kasgharian, Michael

AU - O'Brien, Kevin

AU - Ferreira, Carlos R

AU - Atwal, Paldeep S

AU - Jain, Mahim

AU - Hammers, Alexander

AU - Charles-Edwards, Geoffrey

AU - Choe, Chi-Un

AU - Isbrandt, Dirk

AU - Cebrian-Serrano, Alberto

AU - Davies, Ben

AU - Sandford, Richard N

AU - Pugh, Christopher

AU - Konecki, David S

AU - Povey, Sue

AU - Bockenhauer, Detlef

AU - Lichter-Konecki, Uta

AU - Gahl, William A

AU - Unwin, Robert J

AU - Warth, Richard

AU - Kleta, Robert

N1 - Copyright © 2018 by the American Society of Nephrology.

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1681/ASN.2017111179

DO - 10.1681/ASN.2017111179

M3 - SCORING: Journal article

C2 - 29654216

VL - 29

SP - 1849

EP - 1858

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 7

ER -