Identificatie van het gen voor het hyper-IgD-syndroom: een schoolvoorbeeld van moderne genetica

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS