Cloning and Sequence of the Human Gene for P450cl7 (Steroid 17α-Hydroxylase/17,20 Lyase): Similarity with the Gene for P450c21

Picado-Leonard, James; Miller, Walter L.

doi:10.1089/dna.1987.6.439

Cited by 391 publications

(167 citation statements)

References 34 publications

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“…The CYP17A1 gene encoding this enzyme is mapped to chromosome 10q24.3 (3)(4)(5). To date, more than 50 deleterious mutations in the CYP17A1 gene have been reported to cause either combined or isolated 17a-hydroxylase/17,20-lyase deficiency (17OHD), including missense mutations, deletions, insertions, and singlebase changes in the CYP17A1 gene.…”

Section: Introductionmentioning

confidence: 99%

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

Qiao¹,

Han²,

Liu³

et al. 2011

European Journal of Endocrinology

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Background: 17a-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. Objective: A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. Methods and results: Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263GOA) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. Conclusion: This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.

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Section: Introductionmentioning

confidence: 99%

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

Qiao¹,

Han²,

Liu³

et al. 2011

European Journal of Endocrinology

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“…Thereafter, the specific steroid that is synthesized by a particular tissue depends upon the differential expression of additional steroidogenic enzymes. The conversion of pregnenolone and progesterone to their 17␣-hydroxylated products and then to either dehydroepiandrosterone (DHEA) or androstenedione, respectively, is mediated by a single microsomal enzyme, P450c17 (33,34,48), encoded by a single gene (22,39). The pattern of P450c17 expression in steroidogenic tissues is species specific: it is expressed in the human adrenal and gonad but not placenta (9,11,15,44), and it is expressed in the rodent gonad and placenta but not adrenal (19,23,25).…”

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confidence: 99%

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Bair

Mellon

2004

Molecular and Cellular Biology

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Dehydroepiandrosterone (DHEA), a 19-carbon precursor of sex steroids, is abundantly produced in the human but not the mouse adrenal. However, mice produce DHEA and DHEA-sulfate (DHEAS) in the fetal brain. DHEA stimulates axonal growth from specific populations of mouse neocortical neurons in vitro, while DHEAS stimulates dendritic growth from those cells. The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17␣-hydroxylase and 17,20-lyase activities. We hypothesized that P450c17-knockout mice would have disordered sex steroid synthesis and disordered brain DHEA production and thus provide phenotypic clues about the functions of DHEA in mouse brain development. We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells. Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17 ؊/؊ zygotes died by embryonic day 7, prior to gastrulation. The cause of this early lethality is unknown, as there is no known function of fetal steroids at embryonic day 7. Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown. Enzyme assays of wild-type embryos showed a rapid rise in 17-hydroxylase activity between E6 and E7 and the presence of C 17,20 -lyase activity at E7. Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17 ؊/؊ fetuses. Treatment of normal pregnant females with pellets releasing pregnenolone or progesterone did not cause fetal demise. These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development.

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“…CYP17 gene is located 10q24.32 (Fan et al, 1992). This gene has 6569 base pair and 8 exons (Picado-Leonard and Miller, 1987) and codes for P450c17 that catalyzes 17a-hydroxylase and 17,20-lyase reaction in metabolism pathway of testosterone (Barnes et al, 1991). A2 allele is known with T/C transition in -34 5´UTR of transcript and it is considered that creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression of CYP17 gene (Carey et al, 1994) but by the now, role of this polymorphism in vivo has not been clearly known.…”

Section: Introductionmentioning

confidence: 99%

A2 Allele Polymorphism of the CYP17 Gene and Prostate Cancer Risk in an Iranian Population

Karimpur-Zahmatkesh¹,

Farzaneh²,

Pouresmaeili³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Studies have shown that alterations of steroid hormone metabolism, particularly involving testosterone, affect the risk of prostate cancer. Therefore, genetic variation in genes of enzymes which are involved could be of importance. The gene most interest is CYP17, whose enzyme product has an essential role in testosterone hormone synthesis. Some studies have indicated that the A2 allele polymorphism of CYP17 associated with increased risk of prostate cancer that could be affected by ethnicity. Therefore, the aim of this study was determination of presence or absence of the A2 allele in patients with prostate cancer. Materials and Methods: We studied the association of A2 allele and prostate cancer among 74 patients with prostate cancer and 128 healthy men which were referred to hospitals of SBMU. Results: This study revealed a significant association between prostate cancer risk and the A2 allele in an Iranian population so that A1A2 and A2A2 genotypes were more common in cases than controls with P-values of 0.029 and 0.010, respectively. Conclusions: Results of our study support a possible role of the A2 allele in sporadic prostate cancer development in Iran, in line with findings elsewhere.

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Cloning and Sequence of the Human Gene for P450cl7 (Steroid 17α-Hydroxylase/17,20 Lyase): Similarity with the Gene for P450c21

Cited by 391 publications

References 34 publications

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

A2 Allele Polymorphism of the CYP17 Gene and Prostate Cancer Risk in an Iranian Population

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