(from the application): Mevalonate kinase (MvK) catalyzes the first committed step in cholesterol and isoprene synthesis, and is the site of two human enzyme deficiencies, severe mevalonic aciduria (MA) and hyperimmunoglobulin D syndrome (HIDS), both manifesting autoinflammatory disease. The investigators'long-term objective is to understand the pleiotropic pathophysiology associated with MA and HIDS, and the potential role of MvK in diverse cellular processes. To work toward this objective, they have utilized a gene-trap approach to ablate MvK in the mouse. Whereas MvK-/- mice appear to die embryonically, MvK+/- mice survive and manifest a hyperinflammatory phenotype reminiscent of that seen in both HIDS and MA patients, but absent the additional neurological sequelae observed in MA patients.
The specific aim i s to identify the embryological age of fetal loss for MvK-/- mice using the investigators'current gene-trap construct, assess structural anomalies that might be present and determine whether implantation occurs, and then generate a viable MvK-/- mouse via knock-in of specific human MvK missense mutations. The rationale is that HIDS patients manifest higher residual MvK enzyme activity (1.4-5.7% of control) than MA patients (0-0.2% of control). Thus, the investigators speculate that MvK+/- animals (with ~50% of MvK+/+ enzyme activity) might more readily recapitulate the HIDS phenotype, whereas it will require greater knock-down of murine MvK activity to recapitulate the human MA phenotype, but not total ablation via gene deletion. The hypothesis is that knock-in of specific human MvK missense mutations will produce a viable MvK-/- mouse that recapitulates the neurological phenotype and immune disease observed in MA patients. The investigators will adhere to a cohort control design, with age- and gender-matched controls for all studies, and will employ standard methods of animal husbandry, embryo isolation and characterization, and gene targeting. MvK+/- and MvK-/- mice will help unravel pathophysiology associated with MA and HIDS, while providing tools for characterization of other autoinflammatory disorders as well as monogenic/complex genetic diseases in which cholesterol pathway function has been implicated.
| Simon, Anna; Drenth, Joost P H; Matern, Dietrich et al. (2013) Long chain fatty acid (Lcfa) abnormalities in hyper Igd syndrome (Hids) and Familial Mediterranean Fever (Fmf): new insight into heritable periodic fevers. Mol Genet Metab 108:166-71 |
| Hager, Elizabeth J; Piganelli, Jon D; Tse, Hubert M et al. (2012) Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). J Inherit Metab Dis 35:159-68 |
| Skvorak, Kristen J; Hager, Elizabeth J; Arning, Erland et al. (2009) Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD). Biochim Biophys Acta 1792:1004-10 |
