Reichold, Markus, Klootwijk, Enriko D., Reinders, Joerg, Otto, Edgar A., Milani, Mario ORCID: 0000-0001-6098-3991, 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 ORCID: 0000-0002-4181-2676, 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 ORCID: 0000-0001-9530-4848, 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 ORCID: 0000-0001-5878-941X, Lichter-Konecki, Uta, Gahl, William A., Unwin, Robert J., Warth, Richard ORCID: 0000-0001-6084-0659 and Kleta, Robert (2018). Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. J. Am. Soc. Nephrol., 29 (7). S. 1849 - 1859. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reichold, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klootwijk, Enriko D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinders, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Otto, Edgar A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milani, MarioUNSPECIFIEDorcid.org/0000-0001-6098-3991UNSPECIFIED
Broeker, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laing, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesner, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devi, SulochanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, WeibinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tegtmeier, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sterner, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doellerer, HannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renner, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oefner, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dettmer, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simbuerger, Johann M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witzgall, RalphUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanescu, Horia C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dumitriu, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iancu, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, VakshaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mozere, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tekman, MehmetUNSPECIFIEDorcid.org/0000-0002-4181-2676UNSPECIFIED
Jaureguiberry, GracianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Issler, NaomiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kesselheim, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walsh, Stephen B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gale, Daniel P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howie, Alexander J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martins, Joana R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, Andrew M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kasgharian, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Brien, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreira, Carlos R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Atwal, Paldeep S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jain, MahimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammers, AlexanderUNSPECIFIEDorcid.org/0000-0001-9530-4848UNSPECIFIED
Charles-Edwards, GeoffreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choe, Chi-UnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cebrian-Serrano, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davies, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandford, Richard N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pugh, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konecki, David S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Povey, SueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bockenhauer, DetlefUNSPECIFIEDorcid.org/0000-0001-5878-941XUNSPECIFIED
Lichter-Konecki, UtaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gahl, William A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unwin, Robert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warth, RichardUNSPECIFIEDorcid.org/0000-0001-6084-0659UNSPECIFIED
Kleta, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-180550
DOI: 10.1681/ASN.2017111179
Journal or Publication Title: J. Am. Soc. Nephrol.
Volume: 29
Number: 7
Page Range: S. 1849 - 1859
Date: 2018
Publisher: AMER SOC NEPHROLOGY
Place of Publication: WASHINGTON
ISSN: 1533-3450
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TUBULAR ABSORPTION DEFECT; L-ARGININE; HYPOPHOSPHATEMIC OSTEOMALACIA; CREATINE BIOSYNTHESIS; NLRP3 INFLAMMASOMES; NALP3 INFLAMMASOME; AMINO-ACIDS; ADULT ONSET; FAMILY; FIBROSISMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18055

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