Mevalonate kinase deficiency

Mevalonate kinase deficiency
A patient with mevalonate kinase deficiency at the age of 21 months, displaying characteristic craniofacial features.
Classification and external resources
OMIM	251170
DiseasesDB	29843
MeSH	D054078
[]

Mevalonate kinase deficiency, also called mevalonic aciduria and hyper immunoglobin D syndrome is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids.

It is characterized by an elevated level of immunoglobin D in the blood.

The enzyme is involved in biosynthesis of cholesterols and isoprenoids. The enzyme is necessary for the conversion of mevalonate to mevalonate-5-phosphate in the presence of Mg2+ [Harper’s biochemistry manual]. Mevalonate kinase deficiency causes the accumulation of mevalonate in urine and hence the activity of the enzyme is again reduced Mevalonate kinase deficiency. It was first described as HIDS in 1984.

Mevalonate kinase deficiency is an example of loss-of-function mutation. There is a mutation in the gene which is coding for mevalonate kinase which is at 12q24 locus [1]. There are almost 63 pathological sequence variations which is present throughout the 10 exons. The most common mutations are V377I, I268T, H20P/N and P167L. These mutations are present in 70% of the affected individuals [9]. A person with HIDS has two HIDS-mutations only id the parents of the patients are carriers. The risk of a child of parents who are both carriers to get the disease is 25%. In half of the cases, the child of such parents will be a carrier of the mutation. But a child does not always get the inherited predisposition. The inheritance of genes is purely coincidental. So, either all the children ae unaffected or three-fourth are affected. If the affected individual has both the mutations and he marries an unaffected individual, then the children of the affected individuals won’t be ill but will act as carrier .

Immunoglobin D

Immunoglobulin D (IgD) is a protein produced by a certain type of white blood cells. There are five classes of Immunoglobin like IgG, IgA and IgM, IgE and IgD. They play an important role in the immune system. The function of IgD is still unclear.

There is a relationship between MKD and the interleukin 1beta (IL-Iβ). There is an increased IL-1β secretion and mevalonate kinase deficiency in MKD is most likely mediated by defective protein prenylation (Prenylation refers to addition of hydrophobic residues to proteins) ] and non-sterol isoprenoids, such as farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) are coupled to a target protein, which affects the activity and the cellular location. In a human monocytic MKD model it was found that the deficiency of GGPP leads to overproduction of IL-1β and defective prenylation of RhoA. This causes an increased level of Rac1 and PKB which was affecting the GTPases and B7-Glycoproteins. It was earlier found that Rac1/PI3K/PKB pathway had been linked to the pathogenesis of MKD. The inactivation of RhoA acts an inducer of IL-1β mRNA transcription independent of NLRP3- or caspase-1 activity. Due to defective RhoA there is a formation of defective (elongated and instable) in the cell. If a defective mitochondria it is cleared in the cell by the mechanism of autophagia. But, in MKD the clearance of defective mitochondria from the cytosol is disrupted. As a result, the starts accumulating in the cytosol which binds and activates NLRP3 which is responsible for the production of IL-1β. The activation can be direct or indirect. It can also be activated by reactive oxygen species (ROS). It is known that monocytes and macrophages also produce higher levels of tumor necrosis factor alpha (TNF-α), interleukin 6(IL-6) other than IL-Iβ During the febrile (fever) attacks and during the attacks the C - reactive protein (CRP) also increases. [9]. The CRP is released by liver which causes inflammation[13].

...
Wikipedia