Mevalonate kinase deficiency presenting as recurrent rectal abscesses and perianal fistulae.
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ABSTRACT:
SUBMITTER: Dunn K
PROVIDER: S-EPMC5803340 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Mevalonate kinase deficiency presenting as recurrent rectal abscesses and perianal fistulae.
Dunn Kara K Pasternak Brad B Kelsen Judith R JR Sullivan Kathleen E KE Dawany Noor N Wright Benjamin L BL
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 20171228 2
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Project description:Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.
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Project description: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.
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