Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure

Sandra Pérez-Torras; Aida Mata-Ventosa; Britt Drögemöller; Maja Tarailo-Graovac; Judith Meijer; Rutger Meinsma; Arno G van Cruchten; Wim Kulik; Albert Viel-Oliva; Axel Bidon-Chanal; Colin J Ross; Wyeth W Wassermann; Clara D M van Karnebeek; Marçal Pastor-Anglada; André B P van Kuilenburg

doi:10.1016/j.bbadis.2019.01.013

Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure

Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1182-1191. doi: 10.1016/j.bbadis.2019.01.013. Epub 2019 Jan 15.

Authors

Sandra Pérez-Torras¹, Aida Mata-Ventosa¹, Britt Drögemöller², Maja Tarailo-Graovac³, Judith Meijer⁴, Rutger Meinsma⁴, Arno G van Cruchten⁴, Wim Kulik⁴, Albert Viel-Oliva¹, Axel Bidon-Chanal⁵, Colin J Ross², Wyeth W Wassermann⁶, Clara D M van Karnebeek⁷, Marçal Pastor-Anglada⁸, André B P van Kuilenburg⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Departments of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, the Netherlands.
⁵ Departments 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.
⁶ Departments of Pediatrics and Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, V5Z 4H4 Vancouver, Canada.
⁷ Departments of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, the Netherlands; Departments of Pediatrics and Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, V5Z 4H4 Vancouver, Canada.
⁸ 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. Electronic address: [email protected].
⁹ Departments of Clinical Chemistry, Pediatrics and Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, the Netherlands. Electronic address: [email protected].

PMID: 30658162
DOI: 10.1016/j.bbadis.2019.01.013

Abstract

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 SLC28A1, 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.(Leu17Argfs*34) and c.853_855del; 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.

Keywords: PRF1; Pyrimidine metabolism; Uridine-cytidineuria; hCNT1.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Fatal Outcome
Humans
Infant
Infant, Newborn
Male
Membrane Transport Proteins / deficiency*
Membrane Transport Proteins / genetics
Multiple Organ Failure / genetics
Multiple Organ Failure / metabolism*
Perforin / deficiency*
Perforin / genetics
Phenotype
Purine-Pyrimidine Metabolism, Inborn Errors / genetics
Purine-Pyrimidine Metabolism, Inborn Errors / metabolism*
Pyrimidines / metabolism*

Substances

Membrane Transport Proteins
Pyrimidines
cif nucleoside transporter
Perforin
pyrimidine

Grants and funding

301221/CIHR/Canada