Alt. symbols: LRBP | MK

Approved name: mevalonate kinase
Alt. names: mevalonate kinase (mevalonic aciduria) | LH receptor mRNA-binding protein, mevalonic aciduria

Location: 12q24.11: 109573255 - 109598125 (+)
Gene type: protein_coding, 17 transcripts.

Scores: LoFtool: 0.069800 | pLI: 0.04216140 | LOEUF: 0.545

HGNC: 7530

NCBI: 4598, RefSeq: NG_007702.1

Ensembl: ENSG00000110921.14

LRG_156 | Status: public

OMIM: 251170

Expression | ProteinAtlas

Mevalonate kinase (MVK) is an ubiquitously expressed enzyme with an important function in cholesterol and isoprenoid biosynthesis (PMID: 1967820). Defects in MVK activity lead to depleted levels of geranylgeranyl pyrophosphate, which is an important metabolic intermediate required for the prenylation of NLRP3 and the small GTPases KRas and RhoA, which regulate the pyrin inflammasome by activating protein kinases (PKN1/PKN2) and phosphatidylinositol-3-OH kinase (PI3K) to keep pyrin in an inactive state. Thus, dysregulated protein prenylation in hematopoietic cells results in increased activity of the pyrin and NLRP3 inflammasomes (PMID: 34539662).

AR MKD falls along a phenotypic spectrum encompassing both inborn errors of metabolism and inborn errors of immunity. The milder end of the spectrum is historically known as HIDS [OMIM: 260920], while the more severe end of the spectrum features a systemic metabolic disease called mevalonic aciduria (MA) [OMIM: 610377], in which some patients may exhibit HIDS along with other dysmorphic and neurologic features. Nearly all HIDS-associated variants are missense changes thought to impair protein st ability in a temperature-sensitive manner, while MA-associated variants are generally nonsense mutations or create truncated proteins (PMID: 12444096). Data from the Eurofever registry suggests that MKD affects at least 300 people worldwide, with the majority affected by HIDS. The most frequently occurring MVK mutation (Val377Ile) has been identified exclusively in HIDS patients and, together with Ile268Thr, this accounts for over 50% of HIDS patients in multiple populations. The Dutch population has been reported with a relatively high carrier frequency for MVK mutations, estimated as high as 1:65 from newborn screening samples, even though disease incidence is estimated at closer to ~1:200,000 (PMID: 12634869), suggesting the possibility of reduced penetrance. HIDS is characterized by early childhood onset of episodes of recurrent fever lasting 3 to 7 days associated with abdominal pain, diarrhea, large joint arthralgias or non-erosive arthritis, myalgias, lymphadenopathy, hepatosplenomegaly, increased susceptibility to infections and various mucocutaneous findings in ~70% of patients (PMID: 27213830). These latter include oral aphthae as well as non-specific maculopapular or morbilliform rashes, but urticarial lesions, erythema nodosum, and other more petechial or purpuric vasculitic-type lesions have also been reported. In MA, the inflammatory symptoms may be masked by the more severe neurological manifestations such as cerebellar ataxia, seizures, and/or mental, motor, and growth retardation. Atypical forms include nonsyndromic retinitis pigmentosa (RP), prominent liver or cardiorespiratory disease, IBD, or AA amyloidosis (PMID: 33917151). Symptoms may be triggered by immunization and labs show elevated inflammatory markers and a biochemical signature (mevalonic aciduria during febrile episodes), though this may not always be detected. Stimulated PBMCs from MKD patients produce higher levels of IL-1β compared those from healthy individuals, consistent with the responsiveness to anti-IL-1 therapy seen in HIDS patients (PMID: 29768139), while allogeneic HSCT has been successfully used in MA patients (PMID: 17596604). The most recently recognized MVK-associated disease is porokeratosis, a skin-restricted clinical phenotype of variable penetrance characterized by potentially malignant epidermal keratosis without inflammatory features [OMIM: 175900] (PMID: 22983302). This is thought to arise from a dominantly inherited germline or somatic LOF mutation followed by a postzygotic “second hit” or somatic mutation in the mevalonate biosynthesis pathway (PMID: 31207227). [Load More]