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 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.
Department of Clinical Pathology, Jen-Ai Branch, Taipei City Hospital, Taipei, Taiwan. lls045@yahoo.com.tw
Long-Shyong
LS
Lee
Wei-Jane
WJ
Shu
Chen-Ming
CM
Wu
Chia-Hsing
CH
Hsieh
Su-Mei
SM
Chen
Chaur-Jong
CJ
Hu
Wei-Yi
WY
Chen
Bon-Chu
BC
Chung
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D000483:Alleles; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D035583:Rare Diseases / Q000235:genetics; D017384:Sequence Deletion; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013624:Taiwan / Q000208:ethnology
D013254:Steroid 17-alpha-Hydroxylase