TY - JOUR
T1 - Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency
AU - Politiek, Frouwkje A.
AU - Waterham, Hans R.
N1 - Funding Information: This work was funded in part by a grant from the AMC foundation. Publisher Copyright: © Copyright © 2021 Politiek and Waterham.
PY - 2021/9/3
Y1 - 2021/9/3
N2 - Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
AB - Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
KW - hyper IgD syndrome
KW - isoprenoid biosynthesis
KW - mevalonate kinase deficiency (MKD)
KW - mevalonic aciduria
KW - protein prenylation
UR - http://www.scopus.com/inward/record.url?scp=85115192202&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2021.724991
DO - https://doi.org/10.3389/fimmu.2021.724991
M3 - Review article
C2 - 34539662
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 724991
ER -