Artikel ; Online: Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure.
Biochimica et biophysica acta. Molecular basis of disease
2019 Band 1865, Heft 6, Seite(n) 1182–1191
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 ... ...
| 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. |
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| Mesh-Begriff(e) | 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 | |||||
| Chemische Substanzen | Membrane Transport Proteins ; Pyrimidines ; cif nucleoside transporter ; Perforin (126465-35-8) ; pyrimidine (K8CXK5Q32L) | |||||
| Sprache | Englisch | |||||
| Erscheinungsdatum | 2019-01-15 | |||||
| Erscheinungsland | Netherlands | |||||
| Dokumenttyp | Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 60-7 | |||||
| ISSN | 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399 | |||||
| ISSN (online) | 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 | |||||
| ISSN | 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399 | |||||
| DOI | 10.1016/j.bbadis.2019.01.013 | |||||
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| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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