A NOVEL MUTATION IN THE STEROL 27-HYDROXYLASE GENE OF A PAKISTANI FAMILY WITH AUTOSOMAL RECESSIVE CEREBROTENDINOUS XANTHOMATOSIS

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive dis order of lipid storage with prominent neurologic features. The disease is associated with mutations in CYP27, which encodes mitochondrial st erol 27-hydroxylase, an enzyme that catalyzes the oxidation of sterol intermediates during bile acid synthesis. The loss of this enzyme resu lts in accumulation of cholestanol in the nervous system and other tis sues. Six different mutations have been previously described in CTX. W e analyzed a Pakistani family, which included four affected individual s with clinical characteristics of CTX, for mutations in CYP27. The ex ons of CYP27 in the family DNA were amplified by polymerase chain reac tion (PCR) and analyzed for mutations by band shifts (single stranded conformational polymorphism [SSCP]) and DNA sequencing. The PCR produc t for exon 4 showed an SSCP change in this family. The DNA of affected individuals showed an abnormal mobility pattern interpreted as homozy gous for the mutation. One non-affected sibling was homozygous for the normal migrating pattern, whereas the parents and another non-affecte d sibling were heterozygous. The sequence of exon 4 of affected indivi duals showed a substitution of C to T in codon 237, thus substituting arginine to a stop codon. This mutation would terminate the translatio n, which may result in a protein half the size of the wild type render ing it practically inactive.