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1.
J Am Soc Nephrol ; 32(11): 2885-2899, 2021 11.
Article in English | MEDLINE | ID: mdl-34607910

ABSTRACT

BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.


Subject(s)
Cardiomyopathy, Dilated/genetics , Hypercalciuria/genetics , Kidney Diseases/genetics , Monomeric GTP-Binding Proteins/genetics , Mutation, Missense , Nephrocalcinosis/genetics , Renal Tubular Transport, Inborn Errors/genetics , TOR Serine-Threonine Kinases/metabolism , Cardiomyopathy, Dilated/metabolism , Female , HEK293 Cells , Humans , Hypercalciuria/metabolism , Kidney Diseases/metabolism , Kidney Tubules, Distal/metabolism , Male , Models, Molecular , Natriuresis/genetics , Nephrocalcinosis/metabolism , Pedigree , Protein Conformation , Renal Tubular Transport, Inborn Errors/metabolism , Seizures/genetics , Seizures/metabolism , Signal Transduction , Exome Sequencing , Whole Genome Sequencing
2.
Pediatr Cardiol ; 40(3): 468-476, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30238137

ABSTRACT

Early extubation appears to have beneficial effects on the Fontan circulation. The goal of this study was to assess the impact of extubation on the operating table in comparison with extubation during the first hours after Fontan operation (FO) on the early postoperative course. Between 2013 and 2016, 114 children with a single ventricle heart malformations (mean age, 3.8 ± 2.3 years) underwent FO: 60 patients were extubated in the operating room (ORE) and 54 in the intensive care unit (ICUE) in the median time of 195 min (range 30-515 min) after procedure. Pre-, peri-, and postoperative records were retrospectively analyzed. The hospital survival rate was 100%. One patient from the ORE group needed an immediate reintubation because of laryngospasm. The ORE group showed lower heart rate (106.5 vs. 120.3 bpm; p < 0.001) and lower central venous pressure (10.4 vs. 11.4 mmHg; p = 0.001) than patients in the ICUE group within the first 24 h after FO, as well as higher systolic blood pressure within 7 h after operation (88.6 ± 2.5 vs. 85.6 ± 2.6 mmHg; p = 0.036). The ORE children manifested significantly less pleural effusions during 48 h after FO (38.0 vs. 49.5 ml/kg; p = 0.004), received less intravenous fluid administration within 24 h after FO (54.1 vs. 73.8 ml/kg; p = 0.019), less inotropic support (9.8 vs. 12.8 h of dopamine; p = 0.033), and less antibiotics (4.7 vs. 5.8 days; p = 0.037). ICUE children manifested metabolic acidosis more frequently than the ORE group 3-4 h after FO (p < 0.05). Immediate extubation after FO in comparison with extubation in the ICU appears to be associated with improved hemodynamics and reduced application of therapeutic interventions in the postoperative course.


Subject(s)
Airway Extubation/methods , Fontan Procedure/adverse effects , Heart Defects, Congenital/surgery , Operating Rooms/statistics & numerical data , Airway Extubation/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Intensive Care Units/statistics & numerical data , Intubation, Intratracheal , Male , Postoperative Period , Retrospective Studies , Survival Rate , Time Factors
3.
Thromb Haemost ; 98(2): 283-6, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17721608

ABSTRACT

Neoplastic diseases are often associated with thromboembolic events, however the precise mechanism underlying this observation is a matter of ongoing investigation. It is known that matrixmetalloproteinase-1 (MMP-1) canonically activates the thrombin receptor (PAR-1) and we recently reported that highly metastatic tumor cells of melanoma and colon cancer are secreting matrixmetalloproteinase-1. This tumor-derived MMP1 was shown to be a major activator of endothelial PAR-1, thus leading to endothelial cell activation. As tumor-induced thrombosis is a characteristic of metastazing tumors, we investigated whether tumor-derived supernatant (TUSN) from melanoma and colon cancer may induce adhesion of circulating platelets, an initial step in thrombus formation. A time-course study revealed that TU-SN induces a rapid secretion of von Willebrand factor (VWF) within minutes. Using a novel microfluidic device we analyzed platelet-endothelial interactions in a closed circuit. Immunofluorescence imaging showed that TU-SN rapidly induces platelet-string formation via secreted VWF. We demonstrated that tumor-derived supernatant is a potent agonist inducing platelet adhesion under flow conditions.


Subject(s)
Endothelium, Vascular/pathology , Microfluidics/methods , Neoplasms/complications , Platelet Adhesiveness/drug effects , Thromboembolism/etiology , von Willebrand Factor/metabolism , Cells, Cultured , Colonic Neoplasms/complications , Colonic Neoplasms/metabolism , Culture Media, Conditioned/pharmacology , Humans , Matrix Metalloproteinase 1 , Melanoma/complications , Melanoma/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Receptor, PAR-1
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