Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome

Mevalonic aciduria (MA) and hyperimmunoglobulinaemia D and periodic fever s yndrome (HIDS) are two autosomal recessive inherited disorders both caused by a deficient activity of the enzyme mevalonate kinase (MK) resulting from mutations in the encoding MVK gene. Thus far, disease-causing mutations on ly could be detected by analysis of MVK cDNA. We now describe the genomic o rganization of the human MVK gene. It is 22 kb long and contains 11 exons o f 46 to 837 bp and 10 introns of 379 bp to 4.2 kb. Three intron-exon bounda ries were confirmed from natural splice variants, indicating the occurrence of exon skipping. Sequence analysis of 27 HIDS and MA patients confirmed a ll previously reported genotypes based on cDNA analysis and identified six novel nucleotide substitutions resulting in missense or nonsense mutations, providing new insights in the genotype/phenotype relation between HIDS and MA.