Prevalence of common mutations in the CYP17A1 gene in Chinese Han population
Introduction
The 17α-hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder with an estimated incidence of approximately 1 in 50,000 individuals which is the third after those of 21α-hydroxylase and 11β-hydroxylase deficiency in studies. It was initially described in 1966 by Biglieri et al. in a genotypical female [1] while New reported the first male patient in 1970 [2]. This disease affects both adrenal and gonadal glands which leads to hypertension, hypokalemia, male pseudohermaphroditism or female sexual infantilism, lower plasma cortisol with elevated ACTH, and suppression of renin–angiotensin system and aldosterone production. The disease is caused by mutations in the gene CYP17A1, which is located on chromosome 10q24.3 [3], [4] and consists of eight exons that spans 7003 bases and encodes 508 amino acids [5].
Up to now, more than 80 different mutations of human CYP17A1, genes have been reported around the world, including missense, splicing defect, duplication, insertion, and deletion mutations. These mutations have been known to cause either completely or partially, combined or isolated 17α-hydroxylase/17, 20-lyase enzyme deficiencies, although they are more prevalent in certain ethnic groups, particularly in Brazilians and Japanese.[5], [6] In this study, we report two Han Chinese families with 17α-hydroxylase/17, 20-lyase deficiency carrying heterozygous mutations in the CYP17A1 gene and try to identify the most common mutations of CYP17A1 among Chinese Han population.
Section snippets
Case report
Patient 1 in the first family, 21 years old, phenotypic female sought medical treatment because of primary amenorrhea, severe hypokalemia (2.3 mmol/L) and hypertension (150–170/100–120 mm Hg). Her karyotype was 46, XX. Medical examinations showed sexual infantilism including lack of axillary and pubic hair and breasts development (Tanner stage I). She had prepuberal female external genitalia and no uterus (This was also proved by the ultrasonography). Computed tomography revealed the presence of
Results and discussion
To understand the molecular basis of 17OHD disease, we performed a genetic analysis of two patients and their family members. PCR-direct sequencing revealed two kinds of mutations, of which were: (1) 6436–6438(TAC- > AA), causing amino acid Y329K, 418X (exon 6); (2) 1519–1527 (GACTCTTTC deletion), causing amino acid D487-S488-F489 deletion (exon 8)(Fig. 1). And the mutation of H373L, one of Asian common mutations in accordance with the reports ever before, is also reported in Han Chinese
Sources of funding
This work was supported by grants from National “863” project (No. 2006AA02A406) and “973” project (No. 2007CB512004).
Acknowledgment
We would like to thank Drs. Jinxiao Chu for her efforts in recruiting patients for this study.
References (23)
- et al.
Localization of the human CYP17 gene (cytochrome P450(17 alpha)) to 10q24.3 by fluorescence in situ hybridization and simultaneous chromosome banding
Genomics
(1992) - et al.
A novel compound heterozygous mutation in the CYP17 (P450 17alpha-hydroxylase) gene leading to 17alpha-hydroxylase/17,20-lyase deficiency
Metabolism
(2003) - et al.
Mutation of proline 409 to arginine in the meander region of cytochrome p450c17 causes severe 17 alpha-hydroxylase deficiency
Mol Genet Metab
(2001) - et al.
A complex heterozygous mutation of His373Leu and Asp487–Ser488–Phe489 deletion in human cytochrome P450c17 causes 17alpha-hydroxylase/17,20-lyase deficiency in three Chinese sisters
Mol Cell Endocrinol
(2003) - et al.
Seventeen alpha-hydroxylase deficiency
J Formos Med Assoc
(2006) - et al.
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
Mol Cell Endocrinol
(2006) - et al.
Mutation of histidine 373 to leucine in cytochrome P450c17 causes 17 alpha-hydroxylase deficiency
J Biol Chem
(1993) - et al.
Induction of endometrial cycles and ovulation in a woman with combined 17alpha-hydroxylase/17,20-lyase deficiency due to compound heterozygous mutations on the p45017alpha gene
Fertil Steril
(2000) - et al.
17-hydroxylation deficiency in man
J Clin Invest
(1966) Male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency
J Clin Invest
(1970)
Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23–q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24–q25; and P450c17 to 10q24–q25
DNA Cell Biol
Cited by (24)
Clinical and Genetic Characteristics of 17 α-Hydroxylase/17, 20-Lyase Deficiency: c.985_987delTACinsAA Mutation of CYP17A1 Prevalent in the Chinese Han Population
2021, Endocrine PracticeCitation Excerpt :It's clear that the genotype distributions of CYP17A1 highlight significant regional characteristics. Y329Lfs and c.1459_1467del have been reported to be common in the Han Chinese.14,19–23 Y329Lfs has been reported in 4 of 5 Chinese Han patients with 17-OHD from Henan Province.24
New, recurrent, and prevalent mutations: Clinical and molecular characterization of 26 Chinese patients with 17alpha-hydroxylase/17,20-lyase deficiency
2015, Journal of Steroid Biochemistry and Molecular BiologyThe Principles, Enzymes, and Pathways of Human Steroidogenesis
2015, Endocrinology: Adult and PediatricA review of the literature on common CYP17A1 mutations in adults with 17-hydroxylase/17,20-lyase deficiency, a case series of such mutations among Koreans and functional characteristics of a novel mutation
2014, Metabolism: Clinical and ExperimentalCitation Excerpt :With this notion in mind, D487_F489 deletion has been described as the most common mutation of the CYP17A1 gene, especially in China [31–35,37,38]. Since D487_F489 deletion was first identified in a Thai patient [39], it has been frequently identified in China [31–35,37,38]. Haplotype analysis revealed that the D487_F489del of CYP17A1 came from common ancestors with identical shared haplotypes, suggesting the founder effect in the Asian population [35].
Identifying a novel mutation of CYP17A1 gene from five Chinese 17α-hydroxylase/17, 20-lyase deficiency patients
2013, GeneCitation Excerpt :Previous research suggests that 17αhydroxylase/17,20-lyase deficiency (17OHD) may be the secondary cause of congenital adrenal hyperplasia (CAH) in Brazil, which is caused by CYP17A1 gene mutation and is characterized by hypertension, hypokalemia, the absence of pubertal development and hypergonadotropic hypogonadism in both sexes (Wei et al., 2006). Biglieri first reported this disease in 1966 (Biglieri et al., 1966), and since then, more than 80 inactivating mutations of P450c17 that lead to 17OHD have been reported (Bao et al., 2011). These mutations cause complete or partial, combined or isolated 17α-hydroxylase/17,20-lyase enzyme deficiencies.
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Xunna Bao and Hu Ding contributed equally to this work.