دورية أكاديمية
Molecular and cellular consequences of mevalonate kinase deficiency.
| العنوان: | Molecular and cellular consequences of mevalonate kinase deficiency. |
|---|---|
| المؤلفون: | Politiek FA; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands., Turkenburg M; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands., Henneman L; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands., Ofman R; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands., Waterham HR; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands. Electronic address: h.r.waterham@amsterdamumc.nl. |
| المصدر: | Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Jun; Vol. 1870 (5), pp. 167177. Date of Electronic Publication: 2024 Apr 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam : Elsevier |
| مواضيع طبية MeSH: | Mevalonate Kinase Deficiency*/genetics , Mevalonate Kinase Deficiency*/metabolism , Mevalonate Kinase Deficiency*/pathology , Fibroblasts*/metabolism , Fibroblasts*/pathology, Humans ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency ; Cells, Cultured ; Signal Transduction |
| مستخلص: | Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder associated with recurrent autoinflammatory episodes. The disorder is caused by bi-allelic loss-of-function variants in the MVK gene, which encodes mevalonate kinase (MK), an early enzyme in the isoprenoid biosynthesis pathway. To identify molecular and cellular consequences of MKD, we studied primary fibroblasts from severely affected patients with mevalonic aciduria (MKD-MA) and more mildly affected patients with hyper IgD and periodic fever syndrome (MKD-HIDS). As previous findings indicated that the deficient MK activity in MKD impacts protein prenylation in a temperature-sensitive manner, we compared the subcellular localization and activation of the small Rho GTPases RhoA, Rac1 and Cdc42 in control, MKD-HIDS and MKD-MA fibroblasts cultured at physiological and elevated temperatures. This revealed a temperature-induced altered subcellular localization and activation in the MKD cells. To study if and how the temperature-induced ectopic activation of these signalling proteins affects cellular processes, we performed comparative transcriptome analysis of control and MKD-MA fibroblasts cultured at 37 °C or 40 °C. This identified cell cycle and actin cytoskeleton organization as respectively most down- and upregulated gene clusters. Further studies confirmed that these processes were affected in fibroblasts from both patients with MKD-MA and MKD-HIDS. Finally, we found that, similar to immune cells, the MK deficiency causes metabolic reprogramming in MKD fibroblasts resulting in increased expression of genes involved in glycolysis and the PI3K/Akt/mTOR pathway. We postulate that the ectopic activation of small GTPases causes inappropriate signalling contributing to the molecular and cellular aberrations observed in MKD. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was funded in part by a grant from the AMC foundation. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Actin cytoskeleton; Autoinflammatory disorder; Cell cycle; Metabolic reprogramming; Prenylation; Small GTPases |
| المشرفين على المادة: | 0 (mevalonate kinase) |
| تواريخ الأحداث: | Date Created: 20240418 Date Completed: 20240521 Latest Revision: 20240529 |
| رمز التحديث: | 20240529 |
| DOI: | 10.1016/j.bbadis.2024.167177 |
| PMID: | 38636615 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1879-260X |
|---|---|
| DOI: | 10.1016/j.bbadis.2024.167177 |