Cerebrotendinous xanthomatosis: molecular characterization of two Scandinavian sisters

.  Rystedt E, Olin M, Seyama Y, Buchmann M, Berstad A, Eggertsen G, Björkhem I (Karolinska Institutet, Stockholm, Sweden; OchanomizuUniversity, Tokyo, Japan; Medisinsk avdeling, Haukeland sykehus, Bergen). Cerebrotendinous xanthomatosis: molecular characterization of two Scandinavian sisters (Case report). Journal of Internal Medicine 2002; 252: 259–264. Cerebrotendinous xanthomatosis (CTX) is a hereditary disorder, which is inherited as an autosomally recessive disease, causing production of cholesterol and cholestanol xanthomas and mental retardation. The disease is caused by mutations in the gene for sterol 27‐hydroxylase (CYP27A1). The only CTX patients diagnosed in Scandinavia are two Norwegian sisters from a consanguineous marriage. Here we have characterized the mutation and its functional consequences for the enzyme. Analysis of genomic DNA from cultured fibroblasts identified a base exchange C > T in position 1441, causing arginine at amino acid position 441 to be replaced by tryptophan. The same mutation was introduced by mutagenesis in the complimentary DNA (cDNA) for CYP27, ligated into the expression vector pcDNA4/HisMax and transfected into HEK293 cells. The mutated enzyme had less than 5% of the enzyme activity compared with the native enzyme. No abnormal catalytic products could be identified in the cell culture medium. Probably the mutation affects the haem binding within the holoenzyme. The mutation has also previously been reported in a Japanese family. This is the second example of a CTX‐causing mutation that has been recognized in more than one population.