Elevated core body temperatures may cause bursts of inflammation in individuals with rare autoinflammatory mevalonate kinase deficiency (MKD) via a unique molecular mechanism, reports a study “Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency” published in the Journal of Clinical Investigation on October 3, 2022.
“Our research provides exciting new insights into the underlying physiology of MKD and what may be triggering the inflammatory flares, opening up potential new ways of treating this devastating disorder,” said senior author of the study, Mike Rogers, PhD, head of the bone therapeutics lab at Garvan Institute of Medical Research and professor in the school of clinical medicine at the University of South Wales (UNSW) in Sydney.
The lead author of the study, Marcia Muñoz, PhD, a senior lecturer in the school of clinical medicine at UNSW said, “There has been very little progress in understanding MKD, particularly, the causes of disease flares in patients. One of the main reasons for this lack of knowledge is the absence of appropriate animal models to study the mechanisms of disease”.
MKD patients, usually diagnosed in early childhood, suffer from regular episodes of high fever, rashes, ulcers, swollen lymph nodes and abdominal pain. Patients with severe forms of the disease also suffer from neurological and developmental symptoms that can be fatal. The mechanism underlying the wide spectrum of MKD severity is unclear.
MKD is a recessive genetic disorder caused by mutations in the gene encoding mevalonate kinase, an essential enzyme expressed in all body cells and conserved from bacteria to mammals. The commonest MKD variant occurs when the 377th valine residue is mutated to isoleucine. MKD elevates levels of aberrant cellular proteins which in turn results in immune malfunction and autoinflammation.
“An increase in core body temperature, for example, which could occur with stress or a mild infection, worsened the impact of the mutant enzyme and led to a dramatic build-up of abnormal proteins. This is a likely cause of the inflammatory flares in patients,” said Muñoz.
Roger’s team used gene editing to develop new mouse models that mimic human metabolic MKD mutations. Compound heterozygous mice—mice bearing two different MKD mutations in its two alleles–recapitulated the biochemical phenotype of MKD, with build-up of unprenylated GTPases and increased plasma mevalonic acid. Prenylation, also called isoprenylation or lipidation, occurs when hydrophobic molecules are attached to a biomolecule.
“The disease is caused by having two copies of the mutant gene. There are more than 250 known mutations. So, it’s difficult to predict what combination causes a mild or severe version of MKD,” said Rogers.
The researchers developed mouse models bearing different combinations of MKD mutations with enzyme activities at 10% or 20% of normal levels.
“We discovered that there’s a threshold of enzyme activity. At about 20% activity, there is no disease. Disease starts to appear if enzyme activity falls below this threshold, when the effect on proteins really kicks in,” said Rogers. Elevated core body temperature further decreased enzyme activity to barely detectable levels, leading to high amounts of abnormal proteins.
This observation bears predictive power since levels of aberrant proteins in blood may foreshadow symptom severity. “Clinicians could use this knowledge to help diagnose and manage the disease,” said Rogers.
A protein called NLRP3 plays a role in triggering MKD associated inflammation flares, the team discovered. NLRP3 is implicated in other inflammatory disorders and NLRP3 blockers are in development for clinical use. The current study suggests NLRP3 blockers could also be used to treat MKD.
The study brings a ray of hope for Natalie Billiard, parent of a 13-year-old girl living with MKD. Billiard said, “Fifty years ago my daughter’s illness was termed ‘not compatible with life’. We have come a long way thanks to people like Professor Rogers and the research his team is doing. It’s giving our kids a chance at life.”