Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
| العنوان: | Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency |
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| المؤلفون: | Rob J.W. Arts, David Coman, Michael J. Rogers, Marcia A. Munoz, Julie Jurczyluk, Christina Boros, Sam Mehr, Anna Simon, Pravin Hissaria |
| المصدر: | Frontiers in Immunology, Vol 10 (2019) Frontiers in Immunology, 10 Frontiers in Immunology |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Adult, Male, lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Genotype, Immunology, Protein Prenylation, Biology, Compound heterozygosity, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Prenylation, medicine, Humans, Immunology and Allergy, Phosphorylation, Child, Cells, Cultured, Original Research, Rap1, Mevalonate kinase deficiency, mevalonate kinase, Hereditary Autoinflammatory Diseases, rap1 GTP-Binding Proteins, Mevalonate kinase, HIDS, prenylation, autoinflammation, medicine.disease, Molecular biology, 3. Good health, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, Mevalonic aciduria, Mutation, Leukocytes, Mononuclear, biology.protein, Protein prenylation, Female, Rab, Mevalonate Kinase Deficiency, lcsh:RC581-607, Biomarkers, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Rab GTPase, 030215 immunology |
| الوصف: | The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVKV377I. We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVKV377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD. |
| وصف الملف: | application/pdf |
| تدمد: | 1664-3224 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9bc3ceb14542a58d80ad081ac59942aTest https://doi.org/10.3389/fimmu.2019.01900Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d9bc3ceb14542a58d80ad081ac59942a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16643224 |
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