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Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency

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...

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Autores principales: Munoz, Marcia A., Jurczyluk, Julie, Simon, Anna, Hissaria, Pravin, Arts, Rob J. W., Coman, David, Boros, Christina, Mehr, Sam, Rogers, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702261/
https://www.ncbi.nlm.nih.gov/pubmed/31474985
http://dx.doi.org/10.3389/fimmu.2019.01900
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author Munoz, Marcia A.
Jurczyluk, Julie
Simon, Anna
Hissaria, Pravin
Arts, Rob J. W.
Coman, David
Boros, Christina
Mehr, Sam
Rogers, Michael J.
author_facet Munoz, Marcia A.
Jurczyluk, Julie
Simon, Anna
Hissaria, Pravin
Arts, Rob J. W.
Coman, David
Boros, Christina
Mehr, Sam
Rogers, Michael J.
author_sort Munoz, Marcia A.
collection PubMed
description 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, MVK(V377I). 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 MVK(V377I) 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.
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spelling pubmed-67022612019-08-30 Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency Munoz, Marcia A. Jurczyluk, Julie Simon, Anna Hissaria, Pravin Arts, Rob J. W. Coman, David Boros, Christina Mehr, Sam Rogers, Michael J. Front Immunol Immunology 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, MVK(V377I). 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 MVK(V377I) 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. Frontiers Media S.A. 2019-08-14 /pmc/articles/PMC6702261/ /pubmed/31474985 http://dx.doi.org/10.3389/fimmu.2019.01900 Text en Copyright © 2019 Munoz, Jurczyluk, Simon, Hissaria, Arts, Coman, Boros, Mehr and Rogers. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Munoz, Marcia A.
Jurczyluk, Julie
Simon, Anna
Hissaria, Pravin
Arts, Rob J. W.
Coman, David
Boros, Christina
Mehr, Sam
Rogers, Michael J.
Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title_full Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title_fullStr Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title_full_unstemmed Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title_short Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
title_sort defective protein prenylation in a spectrum of patients with mevalonate kinase deficiency
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702261/
https://www.ncbi.nlm.nih.gov/pubmed/31474985
http://dx.doi.org/10.3389/fimmu.2019.01900
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