Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure
Por:
Perez-Torras S, Mata-Ventosa A, Drögemöller B, Tarailo-Graovac M, Meijer J, Meinsma R, van Cruchten AG, Kulik W, Viel-Oliva A, Bidon-Chanal A, Ross CJ, Wassermann WW, van Karnebeek CDM, Pastor-Anglada M and van Kuilenburg ABP
Publicada:
1 jun 2019
Ahead of Print:
15 ene 2019
Resumen:
Pyrimidine nucleotides are essential for a vast number of cellular processes and dysregulation of pyrimidine metabolism has been associated with a variety of clinical abnormalities. Inborn errors of pyrimidine metabolism affecting enzymes in the pyrimidine de novo and degradation pathway have been identified but no patients have been described with a deficiency in proteins affecting the cellular import of ribonucleosides. In this manuscript, we report the elucidation of the genetic basis of the observed uridine-cytidineuria in a patient presenting with fever, hepatosplenomegaly, persistent lactate acidosis, severely disturbed liver enzymes and ultimately multi organ failure. Sequence analysis of genes encoding proteins directly involved in the metabolism of uridine and cytidine showed two variants c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in SLC28/11, encoding concentrative nucleotide transporter 1 (hCNT1). Functional analysis showed that these variants affected the three-dimensional structure of hCNT1, altered glycosylation and decreased the half-life of the mutant proteins which resulted in impaired transport activity. Co-transfection of both variants, mimicking the trans disposition of c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in the patient, significantly impaired hCNT1 biological function. Whole genome sequencing identified two pathogenic variants c.50delT; p.(Leul7Argfs*34) and c.853_855de1; p.(Lys285del) in the PRF1 gene, indicating that our patient was also suffering from Familial Hemophagocytic Lymphohistiocytosis type 2. The identification of two co-existing monogenic defects might have resulted in a blended phenotype. Thus, the clinical presentation of isolated hCNT1 deficiency remains to be established.
Filiaciones:
Perez-Torras S:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Institut de Recerca Sant Joan de Déu (IR SJD), 08028 Barcelona, Spain
Mata-Ventosa A:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Institut de Recerca Sant Joan de Déu (IR SJD), 08028 Barcelona, Spain
Drögemöller B:
Faculty of Pharmaceutical Sciences, University of British Columbia, V6T 1Z3 Vancouver, British Columbia, Canada
BC Children's Hospital Research Institute, V5Z 4H4 Vancouver, British Columbia, Canada
Tarailo-Graovac M:
Departments of Biochemistry, Molecular Biology and Medical Genetics, Cumming School of Medicine, University of Calgary, T2N 4N1 Calgary, AB, Canada
Alberta Children's Hospital Research Institute, University of Calgary, T2N 4N1 Calgary, AB, Canada
Meijer J:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
Meinsma R:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
van Cruchten AG:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
Kulik W:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
Viel-Oliva A:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Institut de Recerca Sant Joan de Déu (IR SJD), 08028 Barcelona, Spain
Bidon-Chanal A:
Department of Nutrition, Food Science and Gastronomy, School of Pharmacy and Food Science, Institute of Biomedicine (IBUB), Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, 08921 Santa Coloma de Gramenet, Spain
Ross CJ:
Faculty of Pharmaceutical Sciences, University of British Columbia, V6T 1Z3 Vancouver, British Columbia, Canada
BC Children's Hospital Research Institute, V5Z 4H4 Vancouver, British Columbia, Canada
Wassermann WW:
Department of Pediatrics and Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, V5Z 4H4 Vancouver, Canada
van Karnebeek CDM:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
Department of Pediatrics and Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, V5Z 4H4 Vancouver, Canada
Pastor-Anglada M:
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Institut de Recerca Sant Joan de Déu (IR SJD), 08028 Barcelona, Spain
van Kuilenburg ABP:
Department of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Metabolism, 1105 AZ Amsterdam, the Netherlands
Open Access
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