1996 Fiscal Year Final Research Report Summary
Identification of sterol 27 hydroxylase gene mutations in CTX patients
| Project/Area Number |
07457034
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | University of Tokyo |
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Principal Investigator |
SEYAMA Yousuke University of Tokyo, Faculty of Medicine., Professor, 医学部, 教授 (90010082)
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| Co-Investigator(Kenkyū-buntansha) |
KANO Kazutaka University of Tokyo, Faculty of Medicine, Research Associate, 医学部, 助手 (70111507)
KUBOTA Shunichiro University of Tokyo, Faculty of Medicine, Associate Professor, 医学部, 助教授 (00260480)
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| Project Period (FY) |
1995 – 1996
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| Keywords | cerebrotendinous xanthomatosis / cholesterol / cholestanol / sterol 27-hydroxylase gene / point mutation / transfection |
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| Research Abstract |
Cerebrotendinous xathomatosis (CTX), an autosomal recessive lipid-storage hereditary disorder, is caused by mutations in the sterol 27-hydroxylase gene (CYP27). A 24-year-old female Japanese CTX patient and her parents were studied for a CYP27 mutation. Sterol 27-hydroxylase activity in fibroblasts derived from the patient was undetectable, while the activities in fibroblasts from her mother and father were 54% and 41% of the normal level, respectively. Direct sequence analysis showed a missense mutation of A for G substitution in the CYP27 gene at codon 362 (CGT 362Arg to CAT 362His) with a homozygous pattern in the patient, and a heterozygous pattern in the parents. The mutation, which eliminates a normal Hga I endonuclease site at position 1195 of the cDNA and is located at the adrenodoxin binding region of the gene, is most probably responsible for the decreased sterol 27-hydroxylase activity in this Japanese CTX family.
Other three Japanese CTX patients from two unrelated families were also studied genetically. By DNA sequence analysis a novel mutation of A for G substitution at amino acid position 372 (CGG 372Arg to CAG 372Gln) was identified in one of the CTX families. The mutation was also found in two patients from the other family, with a compound heterozygous pattern of A for G substitution at amino acid position 441 (CGG 441Arg to CAG441Gln). The latter mutation was the same as previously reported by our group (J.Lipid Res. 1994,35 : 1031-1039). As the two mutations changed the restriction enzyme sites, rapid screening methods were developed for the detection of the carriers. Transfection of the two mutant cDNAs into COS cells resulted in markedly reduced sterol 27-hydroxylase activity. These results indicate that the three mutations are responsible for the deficiency of the sterol 27-hydroxylase activity in these patients.
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[Publications] Wengen Chen, Shunichiro Kubota, Yukiko Nishimura, Shuichi Nozaki, Shizuya Yamashita, Tsutomu Nakagawa, Kaoru Kameda-Takemura, Masakazu Menju, Yuji Matsuzawa, Ingemar Bjoerkhem, Goesta Eggertsen, and Yousuke Seyama: "Genetic analysis of a Japanese cerebrotendinous xanthomatosis family : identification of a novel mutation in the adrenodoxin binding region of the CYP27gene" Biochimica et Biophysica Acta. 1317. 119-126 (1996)
Description
「研究成果報告書概要(欧文)」より
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