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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.

SUBMITTER: Reichold M

PROVIDER: S-EPMC6050927 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Reichold Markus M Klootwijk Enriko D ED Reinders Joerg J Otto Edgar A EA Milani Mario M Broeker Carsten C Laing Chris C Wiesner Julia J Devi Sulochana S Zhou Weibin W Schmitt Roland R Tegtmeier Ines I Sterner Christina C Doellerer Hannes H Renner Kathrin K Oefner Peter J PJ Dettmer Katja K Simbuerger Johann M JM Witzgall Ralph R Stanescu Horia C HC Dumitriu Simona S Iancu Daniela D Patel Vaksha V Mozere Monika M Tekman Mehmet M Jaureguiberry Graciana G Issler Naomi N Kesselheim Anne A Walsh Stephen B SB Gale Daniel P DP Howie Alexander J AJ Martins Joana R JR Hall Andrew M AM Kasgharian Michael M O'Brien Kevin K Ferreira Carlos R CR Atwal Paldeep S PS Jain Mahim M Hammers Alexander A Charles-Edwards Geoffrey G Choe Chi-Un CU Isbrandt Dirk D Cebrian-Serrano Alberto A Davies Ben B Sandford Richard N RN Pugh Christopher C Konecki David S DS Povey Sue S Bockenhauer Detlef D Lichter-Konecki Uta U Gahl William A WA Unwin Robert J RJ Warth Richard R Kleta Robert R

Journal of the American Society of Nephrology : JASN 20180413 7

<b>Background</b> 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.<b>Methods</b> 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 wit ...[more]

PMID: 29654216

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Project description:BACKGROUND:Progressive bone pain and fracture and abnormal positron emission tomography combined with a computed tomography are main reasons for the oncologists suspecting bone tumor. During the patient's medical treatment, the oncologists' unfamiliarity with adverse reactions to anti-HBV drugs were main reason for the long-term exposure to the drug and the adverse reaction (ADR) experienced by the patient. CASE PRESENTATION:A 63-year-old Chinese man had a 27-month history of progressive generalized bone pain combined with spontaneous fractures. Positron emission tomography combined with a computed tomography, revealed an abnormal increase in ribose metabolism and low positron serum inorganic phosphorus concentration (0.7; 0.78-1.65?mmol/L). Serum creatinine level was 252??mol/L (53-97) ?mol/L, and glomerular filtration rate was 22.79?mL/min/1.73?m2. The patient was referred to a multidisciplinary clinic to clarify the diagnosis of myeloma or bone tumor for further treatment in 2017. His medical history revealed that he had a 30-year history of chronic hepatitis B infection. He had received lamivudine at a daily dose of 100?mg for 19?years (1990 to 2009), which had been changed to adefovir (10?mg/day) owing to lamivudine resistance in 2009. Based on the changes in the patient's laboratory markers and the results of emission computed tomography and other radiographic findings, adefovir-induced hypophosphatemic osteomalacia due to acquired renal Fanconi syndrome was suspected by the clinical pharmacist. Considerable clinical improvement was observed after adefovir discontinuation and the administration of entecavir (1.0?mg, every other day). CONCLUSION:Fanconi syndrome with osteomalacia can develop in patients with chronic hepatitis B infection being treated with adefovir at a conventional low dosage of 10?mg/day. This case highlights the importance of ADR as a differential diagnosis and the need of pharmacists with drug safety expertise expert in the patient management.

Project description:BackgroundRecent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients.MethodsA retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy.ResultsThe mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, n = 22), hyperuricosuria (43%, n = 17) and normoglycaemic glycosuria (30%, n = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43-0.76) versus 0.77 (0.66-1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge.ConclusionIncomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.

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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.

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