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Richard J. Auchus - One of the best experts on this subject based on the ideXlab platform.
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fertility in patients with genetic deficiencies of cytochrome p450c17 cyp17a1 combined 17 hydroxylase 17 20 lyase deficiency and Isolated 17 20 lyase deficiency
Fertility and Sterility, 2014Co-Authors: Courtney Marsh, Richard J. AuchusAbstract:CYP17A1 catalyzes the 17-hydroxylase and 17,20-lyase reactions, regulating the steroid hormones produced by the adrenal glands and gonads. Mutations that compromise all CYP17A1 activities are extremely rare and cause combined 17-hydroxylase/17,20-lyase deficiency. Clinically, combined 17-hydroxylase/17,20-lyase deficiency presents with hypertension, hypokalemia, primary amenorrhea, and sexual infantilism. A few mutations selectively impair 17,20-lyase activity, and some mutations in cofactor proteins cytochrome P450-oxidoreductase and cytochrome b5 also selectively disrupt 17,20-lyase activity. The defect in sex steroid synthesis impairs fertility in both male and female patients when the deficiency is severe. This paper reviews the genetics, steroidogenesis, and fertility impairments associated with these disorders.
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genetic deficiencies of cytochrome p450c17 cyp17a1 combined 17 hydroxylase 17 20 lyase deficiency and Isolated 17 20 lyase deficiency
Genetic Steroid Disorders, 2014Co-Authors: Richard J. AuchusAbstract:Abstract Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, CYP17A1) occupies a critical position in the pathways of human steroidogenesis, regulating the classes of steroid hormones produced by cells of the adrenal glands and gonads. CYP17A1 catalyzes two major reactions: the 17-hydroxylase and 17,20-lyase reactions. Mutations that compromise all CYP17A1 activities cause combined 17-hydroxylase/17,20-lyase deficiency, which presents as hypertension, hypokalemia, and sexual infantilism. A few mutations selectively impair 17,20-lyase activity, and some mutations in cofactor proteins cytochrome P450-oxidoreductase and cytochrome b5 also selectively disrupt 17,20-lyase activity. This chapter reviews the genetics, clinical presentation, management, and history of these disorders.
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cyp17 mutation e305g causes Isolated 17 20 lyase deficiency by selectively altering substrate binding
Journal of Biological Chemistry, 2003Co-Authors: Daniel Sherbet, Dov Tiosano, Kerri M Kwist, Zeev Hochberg, Richard J. AuchusAbstract:Cytochrome p450c17 (CYP17) converts the C21 steroids pregnenolone and progesterone to the C19 androgen precursors dehydroepiandrosterone (DHEA) and androstenedione, respectively, via sequential 17alpha-hydroxylase and 17,20-lyase reactions. Disabling mutations in CYP17 cause combined 17alpha-hydroxylase/17,20-lyase deficiency, but rare missense mutations cause Isolated loss of 17,20-lyase activity by disrupting interactions of redox partner proteins with CYP17. We studied an adolescent male with clinical and biochemical features of Isolated 17,20-lyase deficiency, including micropenis, hypospadias, and gynecomastia, who is homozygous for CYP17 mutation E305G, which lies in the active site. When expressed in HEK-293 cells or Saccharomyces cerevisiae, mutation E305G retains 17alpha-hydroxylase activities, converting pregnenolone and progesterone to 17alpha-hydroxysteroids. However, mutation E305G lacks 17,20-lyase activity for the conversion of 17alpha-hydroxypregnenolone to DHEA, which is the dominant pathway to C19 steroids catalyzed by human CYP17 (the delta5-steroid pathway). In contrast, mutation E305G exhibits 11-fold greater catalytic efficiency (kcat/Km) for the cleavage of 17alpha-hydroxyprogesterone to androstenedione compared with wild-type CYP17. We conclude that mutation E305G selectively impairs 17,20-lyase activity for DHEA synthesis despite an increased capacity to form androstenedione. Mutation E305G provides genetic evidence that androstenedione formation from 17alpha-hydroxyprogesterone via the minor delta4-steroid pathway alone is not sufficient for complete formation of the male phenotype in humans.
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towards a unifying mechanism for cyp17 mutations that cause Isolated 17 20 lyase deficiency
Endocrine Research, 2002Co-Authors: Richard J. Auchus, Manisha GuptaAbstract:Cytochrome P450c17 (CYP17) is a single hemoprotein that catalyzes both the 17alpha-hydroxylase and 17,20-lyase reactions in all species thus far examined. Severe defects in CYP17 cause classical 17-hydroxylase deficiency, but other defects result in partial or selective deficiency states. One such variant is the syndrome of Isolated 17,20-lyase deficiency. Recent detailed studies of the biochemical properties of the mutant CYP17 enzymes from patients with Isolated 17,20-lyase deficiency demonstrate that alterations in the interaction of CYP17 with its redox partner proteins P450-oxidoreductase and cytochrome b5 form the biochemical basis for these selective enzyme defects. Site-directed mutagenesis studies have confirmed that neutralization of any of several positive charges on the redox partner binding surface results in selective disruption of 17,20-lyase activity. In one case diagnosed as Isolated 17,20-lyase deficiency, the identified mutation did not map to the redox partner binding surface; however, we have shown that this mutation cannot be the cause of Isolated 17,20-lyase deficiency in this patient. These consistent results have prompted us to propose a paradigm in which neutralization of positive charges in the redox partner binding surface of CYP17 may be the predominant if not sole mechanism leading to Isolated 17,20-lyase deficiency.
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pitfalls in characterizing p450c17 mutations associated with Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Manisha Gupta, David H Geller, Richard J. AuchusAbstract:The cytochrome P450c17 enzyme system performs both the 17alpha-hydroxylase and 17,20-lyase reactions in the human adrenal glands and gonads. This 17,20-lyase activity is required for the biosynthesis of dehydroepiandrosterone, the C(19) precursor of sex steroids. Considerable evidence supports the idea that the 17,20-lyase activity of this system is particularly sensitive to alterations in the interactions between P450c17 and its cofactor proteins P450-oxidoreductase and cytochrome b(5). We have described two patients with the clinical phenotype of Isolated 17,20-lyase deficiency in whom single amino acid replacement mutations in the redox partner binding site of P450c17 (R347H and R358Q) selectively ablate 17,20-lyase activity while preserving most 17alpha-hydroxylase activity. We have shown by computer modeling and detailed biochemical studies that mutations R347H and R358Q impair the interactions of P450c17 with P450-oxidoreductase and cytochrome b(5) (redox partners). Another mutation reported to cause Isolated 17,20-lyase deficiency (F417C) does not map within the redox partner binding site, but might nonetheless alter the interaction of the mutant protein with redox partners. To study the interaction of the F417C mutation with P450 oxidoreductase and cytochrome b(5), we expressed the cDNA for this protein in yeast microsomes, a heterologous expression system in which the composition of redox partner proteins can be varied systematically. Although the full-length protein was expressed in quantities comparable to those of wild-type P450c17 in this system, the F417C mutation did not form a classical P450 difference spectrum and was devoid of both 17alpha-hydroxylase and 17,20-lyase activities. To ensure that this result was not unique to the yeast expression system, we also expressed wild-type P450c17 and the F417C mutation in COS-7 cells, and we again found that the F417C mutation was expressed, but was not active. To conclusively demonstrate that a particular mutation in P450c17 causes Isolated 17,20-lyase deficiency, accurate enzymatic studies of the mutant protein must reproducibly show activities consistent with the diagnosis. Mutations R347H and R358Q are the only two such mutations found in humans proven to cause Isolated 17,20-lyase deficiency.
M Zachmann - One of the best experts on this subject based on the ideXlab platform.
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a single amino acid substitution in the putative redox partner binding site of p450c17 as cause of Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: A Biasonlauber, Esther Leiberman, M ZachmannAbstract:The molecular basis of Isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with Isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes th...
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a single amino acid substitution in the putative redox partner binding site of p450c17 as cause of Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: A Biasonlauber, Esther Leiberman, M ZachmannAbstract:The molecular basis of Isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with Isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes the synthesis of a protein that retains 17 alpha-hydroxylase activity but virtually no 17,20-lyase activity. Experiments based on the use of an electron donor independent from enzyme binding (iodosobenzene) demonstrated that the addition of electrons restores, at least in part, in vitro 17,20-lyase activity, with no significant influence on the 17 alpha-hydroxylase activity. This suggests that the electron transfer system plays a major role in the differential regulation of the two P450c17 activities. This is the first case of mutated CYP17 in which the in vitro model corresponds to the in vivo situation.
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molecular basis of apparent Isolated 17 20 lyase deficiency compound heterozygous mutations in the c terminal region arg 496 cys gln 461 stop actually cause combined 17 alpha hydroxylase 17 20 lyase deficiency
Biochimica et Biophysica Acta, 1992Co-Authors: Toshihiko Yanase, M Zachmann, Michael R Waterman, J S D Winter, Evan R Simpson, Masaaki KagimotoAbstract:The molecular defect in a reported case of Isolated 17,20-lyase deficiency in a 46XY individual has been elucidated. The patient was found to be a compound heterozygote, carrying two different mutant alleles in the CYP17 gene. One allele contains a point mutation of arginine (CGC) to cysteine (TGC) at amino acid 496 in exon 8. The second allele contains a stop codon (TAG) in place of glutamine (CAG) at position 461 in exon 8 which is located 19 amino acids to the carboxy-terminal side of the P-450(17) alpha heme binding cysteine. COS-1 cells transfected with cDNAs containing one or the other of these mutations showed dramatically reduced 17 alpha-hydroxylase and 17,20-lyase activities relative to cells transfected with the wild type P-450(17) alpha cDNA. While the in vitro data in COS 1 cells can explain the patient's physical phenotype, with female external genitalia, it was somewhat discordant with the clinical expression of Isolated 17,20-lyase deficiency with relative preservation of 17 alpha-hydroxylase activity in vivo. In addition to the expression studies of these two examples of mutants in the C-terminal region of cytochrome P-450(17) alpha, a third mutant cDNA construct containing a 4-base duplication at codon 480 previously found in patients with combined 17 alpha-hydroxylase/17,20-lyase deficiency was also expressed in COS-1 cells. This expressed protein was completely inactive with respect to both activities, supporting the biochemical findings in serum and in vitro biochemical data obtained using a testis from the patient. The results from these patients clearly indicate the importance of the C-terminal region of human P-450(17) alpha in its enzymatic activities.
Walter L Miller - One of the best experts on this subject based on the ideXlab platform.
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the molecular basis of Isolated 17 20 lyase deficiency
Endocrine Research, 1998Co-Authors: Walter L Miller, David H Geller, Richard J. AuchusAbstract:Human P450c17 catalyzes the 17alpha-hydroxylation of pregnenolone to 17OH pregnenolone and of progesterone to 17alpha-OH progesterone; the same P450c17 enzyme also catalyzes 17,20 lyase activity on the same active site, converting 17OH-pregnenolone to DHEA. Rodent and porcine P450c17 also catalyze 17,20 lyase activity with delta4 substrates, converting 17OH-progesterone to delta4 androstenedione, but human P450c17 catalyzes this reaction very inefficiently, so that virtually all human C19 sex steroids are made via 17OH pregnenolone and DHEA. P450c17 is encoded by a single gene and a single species of mRNA. Many mutations of this gene have been described, but until recently all of these either entirely eliminated both 17alpha-hydroxylase and 17,20 lyase activity, or affected each activity equivalently. We have identified and characterized the first patients with P450c17 mutations that selectively ablate 17,20 lyase activity while retaining 17alpha-hydroxylase activity. Through a combination of enyzmologic experiments in transfected mammalian cells and in genetically manipulated yeast, plus a computer model of human P450c17, we have proven that the responsible mutations, R347H and R358Q lie in the redox-partner binding site of P450c17. This site, through which P450c17 interacts with P450 oxidoreductase to receive the electrons needed for catalysis, can be allosterically influenced by cytochrome b5. These two mutations have contributed substantially to our understanding of the mechanisms by which 17alpha-hydroxylase and 17,20 lyase activities are regulated independently, and thus have contributed to the study of regulated 17,20 lyase activity in adrenarche, aging, and the polycystic ovary syndrome.
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the genetic and functional basis of Isolated 17 20 lyase deficiency
Nature Genetics, 1997Co-Authors: David H Geller, Richard J. Auchus, Berenice B Mendonca, Walter L MillerAbstract:Human male sexual differentiation requires production of fetal testicular testosterone, whose biosynthesis requires steroid 17,20-lyase activity. Patients with putative Isolated 17,20-lyase deficiency have been reported. The existence of true Isolated 17,20-lyase deficiency, however, has been questioned because 17 alpha-hydroxylase and 17,20-lyase activities are catalyzed by a single enzyme, microsomal cytochrome P450c17, and because the index case of apparent Isolated 17,20-lyase deficiency had combined deficiencies of both activities. We studied two patients with clinical and hormonal findings suggestive of Isolated 17,20-lyase deficiency. We found two patients homozygous for substitution mutations in CYP17, the gene encoding P450c17. When expressed in COS-1 cells, the mutants retained 17 alpha-hydroxylase activity but had minimal 17,20-lyase activity. Substrate competition experiments suggested that the mutations did not alter the enzyme's substrate-binding capacity, but co-transfection of cells with P450 oxidoreductase, the electron donor used by P450c17, indicated that the mutants had a diminished ability to interact with redox partners. Computer-graphic modelling of P450c17 suggests that both mutations lie in or near the redox-partner binding site, on the opposite side of the haem from the substrate-binding pocket. These mutations alter electrostatic charge distribution in the redox-partner binding site, so that electron transfer for the 17,20-lyase reaction is selectively lost or diverted to uncoupling reactions. These are the first proven cases of Isolated 17,20-lyase deficiency, and they demonstrate a novel mechanism for loss of enzymatic activity.
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the molecular basis of Isolated 17 20 lyase deficiency 519
Pediatric Research, 1996Co-Authors: David H Geller, Berenice B Mendonca, Walter L MillerAbstract:Human P450c17 catalyzes the 17α-hydroxylation of pregnenolone to 17OH pregnenolone and of progesterone to 17α-OH progesterone; the same P450c17 enzyme also catalyzes 17,20 lyase activity on the sam...
David H Geller - One of the best experts on this subject based on the ideXlab platform.
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pitfalls in characterizing p450c17 mutations associated with Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Manisha Gupta, David H Geller, Richard J. AuchusAbstract:The cytochrome P450c17 enzyme system performs both the 17alpha-hydroxylase and 17,20-lyase reactions in the human adrenal glands and gonads. This 17,20-lyase activity is required for the biosynthesis of dehydroepiandrosterone, the C(19) precursor of sex steroids. Considerable evidence supports the idea that the 17,20-lyase activity of this system is particularly sensitive to alterations in the interactions between P450c17 and its cofactor proteins P450-oxidoreductase and cytochrome b(5). We have described two patients with the clinical phenotype of Isolated 17,20-lyase deficiency in whom single amino acid replacement mutations in the redox partner binding site of P450c17 (R347H and R358Q) selectively ablate 17,20-lyase activity while preserving most 17alpha-hydroxylase activity. We have shown by computer modeling and detailed biochemical studies that mutations R347H and R358Q impair the interactions of P450c17 with P450-oxidoreductase and cytochrome b(5) (redox partners). Another mutation reported to cause Isolated 17,20-lyase deficiency (F417C) does not map within the redox partner binding site, but might nonetheless alter the interaction of the mutant protein with redox partners. To study the interaction of the F417C mutation with P450 oxidoreductase and cytochrome b(5), we expressed the cDNA for this protein in yeast microsomes, a heterologous expression system in which the composition of redox partner proteins can be varied systematically. Although the full-length protein was expressed in quantities comparable to those of wild-type P450c17 in this system, the F417C mutation did not form a classical P450 difference spectrum and was devoid of both 17alpha-hydroxylase and 17,20-lyase activities. To ensure that this result was not unique to the yeast expression system, we also expressed wild-type P450c17 and the F417C mutation in COS-7 cells, and we again found that the F417C mutation was expressed, but was not active. To conclusively demonstrate that a particular mutation in P450c17 causes Isolated 17,20-lyase deficiency, accurate enzymatic studies of the mutant protein must reproducibly show activities consistent with the diagnosis. Mutations R347H and R358Q are the only two such mutations found in humans proven to cause Isolated 17,20-lyase deficiency.
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the molecular basis of Isolated 17 20 lyase deficiency
Endocrine Research, 1998Co-Authors: Walter L Miller, David H Geller, Richard J. AuchusAbstract:Human P450c17 catalyzes the 17alpha-hydroxylation of pregnenolone to 17OH pregnenolone and of progesterone to 17alpha-OH progesterone; the same P450c17 enzyme also catalyzes 17,20 lyase activity on the same active site, converting 17OH-pregnenolone to DHEA. Rodent and porcine P450c17 also catalyze 17,20 lyase activity with delta4 substrates, converting 17OH-progesterone to delta4 androstenedione, but human P450c17 catalyzes this reaction very inefficiently, so that virtually all human C19 sex steroids are made via 17OH pregnenolone and DHEA. P450c17 is encoded by a single gene and a single species of mRNA. Many mutations of this gene have been described, but until recently all of these either entirely eliminated both 17alpha-hydroxylase and 17,20 lyase activity, or affected each activity equivalently. We have identified and characterized the first patients with P450c17 mutations that selectively ablate 17,20 lyase activity while retaining 17alpha-hydroxylase activity. Through a combination of enyzmologic experiments in transfected mammalian cells and in genetically manipulated yeast, plus a computer model of human P450c17, we have proven that the responsible mutations, R347H and R358Q lie in the redox-partner binding site of P450c17. This site, through which P450c17 interacts with P450 oxidoreductase to receive the electrons needed for catalysis, can be allosterically influenced by cytochrome b5. These two mutations have contributed substantially to our understanding of the mechanisms by which 17alpha-hydroxylase and 17,20 lyase activities are regulated independently, and thus have contributed to the study of regulated 17,20 lyase activity in adrenarche, aging, and the polycystic ovary syndrome.
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the genetic and functional basis of Isolated 17 20 lyase deficiency
Nature Genetics, 1997Co-Authors: David H Geller, Richard J. Auchus, Berenice B Mendonca, Walter L MillerAbstract:Human male sexual differentiation requires production of fetal testicular testosterone, whose biosynthesis requires steroid 17,20-lyase activity. Patients with putative Isolated 17,20-lyase deficiency have been reported. The existence of true Isolated 17,20-lyase deficiency, however, has been questioned because 17 alpha-hydroxylase and 17,20-lyase activities are catalyzed by a single enzyme, microsomal cytochrome P450c17, and because the index case of apparent Isolated 17,20-lyase deficiency had combined deficiencies of both activities. We studied two patients with clinical and hormonal findings suggestive of Isolated 17,20-lyase deficiency. We found two patients homozygous for substitution mutations in CYP17, the gene encoding P450c17. When expressed in COS-1 cells, the mutants retained 17 alpha-hydroxylase activity but had minimal 17,20-lyase activity. Substrate competition experiments suggested that the mutations did not alter the enzyme's substrate-binding capacity, but co-transfection of cells with P450 oxidoreductase, the electron donor used by P450c17, indicated that the mutants had a diminished ability to interact with redox partners. Computer-graphic modelling of P450c17 suggests that both mutations lie in or near the redox-partner binding site, on the opposite side of the haem from the substrate-binding pocket. These mutations alter electrostatic charge distribution in the redox-partner binding site, so that electron transfer for the 17,20-lyase reaction is selectively lost or diverted to uncoupling reactions. These are the first proven cases of Isolated 17,20-lyase deficiency, and they demonstrate a novel mechanism for loss of enzymatic activity.
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the molecular basis of Isolated 17 20 lyase deficiency 519
Pediatric Research, 1996Co-Authors: David H Geller, Berenice B Mendonca, Walter L MillerAbstract:Human P450c17 catalyzes the 17α-hydroxylation of pregnenolone to 17OH pregnenolone and of progesterone to 17α-OH progesterone; the same P450c17 enzyme also catalyzes 17,20 lyase activity on the sam...
A Biasonlauber - One of the best experts on this subject based on the ideXlab platform.
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a single amino acid substitution in the putative redox partner binding site of p450c17 as cause of Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: A Biasonlauber, Esther Leiberman, M ZachmannAbstract:The molecular basis of Isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with Isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes th...
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a single amino acid substitution in the putative redox partner binding site of p450c17 as cause of Isolated 17 20 lyase deficiency
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: A Biasonlauber, Esther Leiberman, M ZachmannAbstract:The molecular basis of Isolated 17,20-lyase deficiency was clarified in a newborn male patient from Israel with micropenis, undescended testes, and hormonal pattern consistent with Isolated 17,20-lyase deficiency. Analysis of the CYP17 gene revealed the presence of a compound heterozygosity. One allele carries a single base pair deletion (T at position 198 in exon 1) leading to a frame shift with the introduction of a premature stop codon, TGA, at residue 74 in place of Val. The other allele bears a missense mutation due to a single base change, T to G, which substitutes Phe417 with Cys. The proof of heterozygosity was possible via amplification and direct sequencing of genomic DNA fragments from the parents and the healthy brother of the index case. We could demonstrate that the mother is the carrier of the nonsense mutation and the father of the missense mutation. The brother carries two normal alleles for the CYP17 gene. The nonsense mutation gives no functional product. The missense mutation causes the synthesis of a protein that retains 17 alpha-hydroxylase activity but virtually no 17,20-lyase activity. Experiments based on the use of an electron donor independent from enzyme binding (iodosobenzene) demonstrated that the addition of electrons restores, at least in part, in vitro 17,20-lyase activity, with no significant influence on the 17 alpha-hydroxylase activity. This suggests that the electron transfer system plays a major role in the differential regulation of the two P450c17 activities. This is the first case of mutated CYP17 in which the in vitro model corresponds to the in vivo situation.
