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J Am Soc Nephrol. 2018 Jul;29(7):1849-1858. doi: 10.1681/ASN.2017111179. Epub 2018 Apr 13.

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

Author information

1
Medical Cell Biology.
2
Centre for Nephrology and.
3
Institute of Functional Genomics.
4
Division of Nephrology and.
5
Italian National Research Council (CNR), Institute of Biophysics, Milan, Italy.
6
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
7
Department of Internal Medicine III, and.
8
Molecular and Cellular Anatomy, University Regensburg, Regensburg, Germany.
9
Institute of Anatomy, University of Zurich, Zurich, Switzerland.
10
Department of Pathology, Yale University, New Haven, Connecticut.
11
NHGRI, National Institutes of Health, Bethesda, Maryland.
12
Mayo Clinic, Jacksonville, Florida.
13
Department of Bone and OI, Kennedy Krieger Institute, Baltimore, Maryland.
14
King's College London and Guy's and St. Thomas' PET Centre, London, United Kingdom.
15
Medical Physics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
16
Department of Neurology, University Hamburg, Hamburg, Germany.
17
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Research Group Experimental Neurophysiology, Bonn, Germany, and University of Cologne, Cologne, Germany.
18
Wellcome Centre for Human Genetics and.
19
Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
20
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
21
GeneDX, Gaithersburg, Maryland; and.
22
Genetics, Evolution and Environment, University College London, London, United Kingdom.
23
Division of Medical Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
24
Medical Cell Biology, richard.warth@ur.de r.kleta@ucl.ac.uk.
25
Centre for Nephrology and richard.warth@ur.de r.kleta@ucl.ac.uk.

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:

AGAT; fibrosis; mitochondriopathy; protein deposits; tubulopathy

PMID:
29654216
PMCID:
PMC6050927
[Available on 2019-07-01]
DOI:
10.1681/ASN.2017111179

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