A novel compound heterozygous mutation of K494_V495 deletion plus R496L and D487_F489 deletion in extreme C-terminus of cytochrome P450c17 causes 17alpha-hydroxylase deficiency

17alpha-Hydroxylase deficiency is a rare disease caused by mutation of the CYP17 gene, resulting in hypertension, hypokalemia, female sexual infantilism or male pseudohermaphroditism, low blood cortisol and low plasma renin activity. Herein, we report a female Taiwanese with 17alpha-hydroxylase defi...

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Published inMolecular and cellular endocrinology Vol. 249; no. 1-2; p. 16
Main Authors Lee, Long-Shyong, Shu, Wei-Jane, Wu, Chen-Ming, Hsieh, Chia-Hsing, Chen, Su-Mei, Hu, Chaur-Jong, Chen, Wei-Yi, Chung, Bon-Chu
Format Journal Article
LanguageEnglish
Published Ireland 25.04.2006
Subjects
Adrenal Hyperplasia, Congenital - genetics
Adult
Alleles
Cell Line
DNA Mutational Analysis
Female
Humans
Mutagenesis, Site-Directed
Pedigree
Rare Diseases - genetics
Sequence Deletion
Steroid 17-alpha-Hydroxylase - genetics
Steroid 17-alpha-Hydroxylase - metabolism
Taiwan - ethnology
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Summary:17alpha-Hydroxylase deficiency is a rare disease caused by mutation of the CYP17 gene, resulting in hypertension, hypokalemia, female sexual infantilism or male pseudohermaphroditism, low blood cortisol and low plasma renin activity. Herein, we report a female Taiwanese with 17alpha-hydroxylase deficiency. The CYP17 genes of this patient and five members of her family were analyzed by PCR-direct sequencing. One allele of the patient contains a 9-bp (c. 1459-1467 GACTCTTTC: D487, S488, F489) deletion, which is prevalent in Southeast Asia. The other allele has a 6-bp (c. 1480-1485 AAGGTG: K494, V495) deletion and an R496L (c. 1487 G>T) missense mutation, which is a novel mutation. Site-directed mutagenesis, in vitro expression and functional analysis in HEK-293T cells showed that this novel mutation [K494_V495 Del; R496L] resulted in complete loss of 17alpha-hydroxylase and 17,20-lyase activity. Thus this novel mutation in the extreme C-terminus abolishes enzyme activity, and when accompanied by a 9-bp deletion at codons 487-489 in the other allele, results in 17alpha-hydroxylase/17,20-lyase deficiency in this patient.
ISSN:0303-7207