ASSIGNMENT OF THE GENE FOR ADRENAL P450cl7 (STEROID 17α-HYDR0XYLASE⁄17,20 LYASE) TO HUMAN CHROMOSOME 10.

Matteson, Karla J.; Picado-Leonard, James; Chung, Bon Chu; Mohandas, T.; Miller, Walter L.

doi:10.1210/jcem-63-3-789

Cited by 159 publications

(49 citation statements)

References 11 publications

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“…Thus, the expression of the "adrenal" form of P450c17 in the testis is not surprising and does not rule out the possibility of another P45OXVII gene encoding a testisspecific P450c17 isozyme. Although it is attractive to hypothesize that one of the other gene sequences detected by low-stringency probing (28) might encode another isozyme of P450c17, no additional testicular P450c17 cDNA clones were detected at these low-stringency conditions. The equivalent intensities of the bands of "adrenal" probe protected from S1-nuclease digestion by adrenal and testicular RNA indicates this is a major, if not the only, form of P450c17 mRNA in the human testis.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues.

Chung¹,

Picado-Leonard²,

Haniu³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

405

164

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P450c17 is the single enzyme mediating both 17a-hydroxylase (steroid 17ai-monooxygenase, EC 1.14.99.9) and 17,20 lyase activities in the synthesis of steroid hormones. It has been suggested that different P450c17 isozymes mediate these activities in the adrenal gland and testis. We sequenced 423 of the 509 amino acids (83%) of the porcine adrenal enzyme; based on this partial sequence, a 128-fold degenerate 17-mer was synthesized and used to screen a porcine adrenal cDNA library. This yielded a 380-base cloned cDNA, which in turn was used to isolate several human adrenal cDNAs. The longest of these, Xhacl7-2, is 1754 base pairs long and includes the full-length coding region, the complete 3'-untranslated region, and 41 bases of the 5'-untranslated region. This cDNA encodes a protein of 508 amino acids having a predicted molecular weight of 57,379.82. High-stringency screening of a human testicular cDNA library yielded a partial clone containing 1303 identical bases. RNA gel blots and nuclease S1-protection experiments confirm that the adrenal and testicular P450c17 mRNAs are indistinguishable. These data indicate that the testis possesses a P450c17 identical to that in the adrenal. The human amino acid sequence is 66.7% homologous to the corresponding regions of the porcine sequence, and the human cDNA and amino acid sequences are 80.1 and 70.3% homologous, respectively, to bovine adrenal P450c17 cDNA. Both comparisons indicate that a central region comprising amino acid residues 160-268 is hypervariable among these species of P450c17. Comparison of the amino acid sequence of P450c17 with two other human steroidogenic cytochromes P450 show much greater homology with P450c21 (28.9%), another microsomal enzyme, than with P450scc (12.3%), a mitochondrial enzyme.Steroid 17a-hydroxylase (steroid 17a-monooxygenase, EC 1.14.99.9) converts pregnenolone to 17-hydroxypregnenolone and converts progesterone to 17-hydroxyprogesterone. These 17-hydroxylated steroids may then be converted by 17,20-lyase to dehydroepiandrosterone and androstenedione, respectively. These latter two steroids are precursors of testosterone and estrogen synthesis while 17-hydroxyprogesterone is a key precursor of cortisol synthesis. Although steroid 17a-hydroxylase and 17,20 lyase activities can be readily distinguished by examination of circulating venous steroidal products (1, 2), studies in both the guinea pig (3) and pig (4) show that both activities reside in a single protein, P450c17. Thus, the P450c17 enzyme is a key branch point in human steroid hormone synthesis, as 17a-hydroxylase activity distinguishes between synthesis of mineralocorticoids (aldosterone) and glucocorticoids (cortisol) and as 17,20 lyase activity distinguishes between synthesis of glucocorticoids and sex steroids. P450c17 is encoded by a gene or genes now termed P45OXVII (5). P450c17 mRNA accumulation is regulated hormonally (6, 7) and developmentally (8). Like P450c21 (steroid 21-hydroxylase), P450c17 is bound to the endoplasmic reticulum and accepts electrons f...

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues.

Chung¹,

Picado-Leonard²,

Haniu³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

405

164

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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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“…P450c17 is encoded by the CYP17A1 gene (OMIM 609300), which is located at 10q24.3 and contains eight exons (3)(4)(5). 17OHD is a rare form of congenital adrenal hyperplasia (CAH) with an estimated incidence of about 1:50,000 newborns (1), which represent 1% of all cases of CAH.…”

Section: Introductionmentioning

confidence: 99%

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil

Belgini

Mello

Baptista

et al. 2010

Arq Bras Endocrinol Metab

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All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C.

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ASSIGNMENT OF THE GENE FOR ADRENAL P450cl7 (STEROID 17α-HYDR0XYLASE⁄17,20 LYASE) TO HUMAN CHROMOSOME 10.

Cited by 159 publications

References 11 publications

Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues.

Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues.

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

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil

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