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A Novel Mutation in the Sterol 27-hydroxylase Gene of a Pakistani Family with Autosomal Recessive Cerebrotendinous Xanthomatosis

From the Department of Neurology (Drs. Ahmed and Hentati, T. Juneja, and Drs. Hung and Siddique), Northwestern University Medical School, Chicago, IL; Department of Medicine (Drs. Afsar, A. Ahmad, Pasha, Ak. Ahmad, Choudhri, Saya, and Siddique), Dow Medical College, Civil Hospital, Karachi, Pakistan; Department of Cell & Molecular Biology (Dr. Siddique), Northwestern University Medical School, Chicago, IL; and Northwestern University Institute for Neuroscience (T. Juneja), Chicago, IL.
Supported by NIH grants no. P01 NS31248 and NS21442 (T.S.), the Les Turner ALS Foundation, Searle Family Center for Neurological Disorders (T.S.), and The Herbert & Florence C. Wenske Foundation (T.S.). W.-H. Hung is a Muriel Heller Fellow.
Received October 23, 1995. Accepted in final form May 14, 1996.
Address correspondence and reprint requests to: Dr. T. Siddique, Northwestern University Medical School, Tarry 13-715, 303 E. Chicago Avenue, Chicago, IL 60611.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of lipid storage with prominent neurologic features.The disease is associated with mutations in CYP27, which encodes mitochondrial sterol 27-hydroxylase, an enzyme that catalyzes the oxidation of sterol intermediates during bile acid synthesis. The loss of this enzyme results in accumulation of cholestanol in the nervous system and other tissues. Six different mutations have been previously described in CTX. We analyzed a Pakistani family, which included four affected individuals with clinical characteristics of CTX, for mutations in CYP27. The exons of CYP27 in the family DNA were amplified by polymerase chain reaction (PCR) and analyzed for mutations by band shifts (single stranded conformational polymorphism [SSCP]) and DNA sequencing. The PCR product for exon 4 showed an SSCP change in this family. The DNA of affected individuals showed an abnormal mobility pattern interpreted as homozygous for the mutation. One non-affected sibling was homozygous for the normal migrating pattern, whereas the parents and another non-affected sibling were heterozygous. The sequence of exon 4 of affected individuals showed a substitution of C to T in codon 237, thus substituting arginine to a stop codon. This mutation would terminate the translation, which may result in a protein half the size of the wild type rendering it practically inactive.

NEUROLOGY 1997;48: 258-260

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