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

Belgini, Daiane R.B.; Mello, Maricilda Palandi de; Baptista, Mónica; Oliveira, Daniel Minutti de; Denardi, Fernandes; Garmes, Heraldo Mendes; Grassiotto, Oswaldo da Rocha; Benetti‐Pinto, Cristina Laguna; Marques-de-Faria, Antônia Paula; Maciel‐Guerra, Andréa Trevas; Guerra‐Júnior, Gil

doi:10.1590/s0004-27302010000800008

Cited by 14 publications

(9 citation statements)

References 19 publications

(29 reference statements)

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“…In the present study, we found 17OHD patients carrying mutations previously described in Brazilian patients [6,25,33] suggesting possible founder effect. The intron 2 IVS2-2A > C mutation occurs at the splice acceptor site leading to disrupt mRNA splicing [25].…”

Section: Discussionsupporting

confidence: 72%

Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency

et al. 2020

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Abstract17-Hydroxylase-deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. The aim of the work was to study clinical, biochemical, and the follow up of 17OHD patients and evaluate the function and structure of CYP17A1 mutations. Brazilian patients (three 46, XX and four 46, XY; 17±1.9 years) with combined 17-hydroxylase/17,20-lyase deficiency were evaluated. CYP17A1 gene was sequenced. Functional analysis was performed transfecting COS7 cells, which were exposed to progesterone or 17α-hydroxypregnolone substrates. Hormones were determined by RIA or LC-MS/MS. Three-dimensional structural modeling was performed by Modeller software. All patients presented prepubertal female external genitalia, primary amenorrhea, hypergonadotrophic hypogonadism, hypokalemic hypertension, decreased cortisol, and increased ACTH and corticosterone levels. Five patients presented previously described mutations: p.W406R/p.W406R, IVS2–2A>C/p.P428L, and p.P428L/p.P428L. Two patients presented the compound heterozygous p.G478S/p.I223Nfs*10 mutations, whose CYP17A1 activity and the three dimensional structural modeling are originally studied in this paper. CYP17A1 activity of p.G478S was 13 and 58% against progesterone and 17-hydroxypregnenolone, respectively. The p.I223Nfs*10 caused a truncated inactive protein. Three-dimensional p.G478S structural modeling showed different internal hydrophobic interaction with W313 and created an additional chain side contact with L476 residue. Due to the rarity of 17OHD, the long term follow up (15.3±3.1 years) of our patients will help endocrinologists on the management of patients with 17OHD. The mutation p.G478S/pI223Nfs*10 led to severe 17OHD and impaired CYP17A1 structure and function. The integration of in silico and in vitro analysis showed how the amino acid changes affected the CYP17A1 activity and contributed to clarify the molecular interactions of CYP17A1.

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Section: Discussionsupporting

confidence: 72%

Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency

et al. 2020

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“…The patients were compound heterozygous carriers for p.Arg362Cys and p.Trp406Arg, previously described as prevalent in Brazil [Martin et al, 2003;Costa-Santos et al, 2004;Belgini et al, 2010]. Their parents were mutation carriers.…”

confidence: 99%

“…DNA from 6 Brazilian patients in whom CYP17A1 mutations had previously been described [Martin et al, 2003;Costa-Santos et al, 2004;Belgini et al, 2010] were resequenced to further characterize 8 polymorphic CYP17A1 sequence variations in the 5 ′ UTR, exon 1, intron 2, intron 5, intron 6, and intron 7 regions, and resulting haplotypes were compared between the Brazilian and Spanish families.…”

Section: Cytogenetic and Molecular Studiesmentioning

confidence: 99%

Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated<b><i> CYP17A1</i></b> Alleles of Brazilian Patients

Fernández‐Cancio¹,

García-García²,

González-Cejudo

et al. 2017

Sex Dev

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17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.

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“…The result is that progesterone and corticosterone are particularly increased in the circulation (Figures 3 and 4) 59 . Of note, in addition to both cortisol and C19 steroids in general being equally depressed in these individuals (see for instance 60; 61 ), 17-hydroxyprogesterone is diminished in contrast to clear elevation of progesterone in these subjects (Figures 3 and 4). …”

Section: ) the Search For A Selective 1720 Lyase Inhibitor – Is It mentioning

confidence: 82%

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

Bird

Abbott

2016

The Journal of Steroid Biochemistry and Molecular Biology

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Given prostate cancer is driven, in part, by its responsiveness to androgens, treatments historically employ methods for their removal from circulation. Approaches as crude as castration, and more recently blockade of androgen synthesis or receptor binding, are still of limited use long term, since other steroids of adrenal origin or tumor origin can supersede that role as the ‘castration resistant’ tumor re-emerges. Broader inhibition of steroidogenesis using relatively nonselective P450 inhibitors such as ketoconazole is not an alternative since a general disruption of steroid biosynthesis is neither safe nor effective. The recent emergence of drugs more selectively targeting CYP17 have been more effective, and yet extension of life has been on the scale of months rather than years. It is now becoming clear this shortcoming arises from the adaptive capabilities of many tumors to initiate local steroid synthesis and/or become responsive to novel early pathway adrenal steroids that are synthesized when lyase activity is not selectively blocked, and ACTH rises in the face of declining cortisol feedback. Abiraterone has been described as a lyase selective inhibitor, yet its use still requires co-administration of prednisone to suppress such a rise of ACTH and fall in cortisol. So is creation of a selective lyase inhibitor even possible? Can C19 steroid production be achieved without a prominent decline in cortisol and corresponding rise in ACTH? Decades of scientific study of CYP17 in humans and nonhuman primates, as well as nature’s own experiments of gene mutations in humans, reveal ‘true’ or ‘isolated’ 17,20 lyase deficiency does quite selectively prevent C19 steroid biosynthesis whereas simple 17 hydroxylase deficiency also suppresses cortisol. We propose these known outcomes of natural mutations should be used to guide analysis of clinical trials and long term outcomes of CYP17 targeted drugs. In this review, we use that framework to re-evaluate the basic and clinical outcomes of many compounds being used or in development for treatment of castration resistant prostate cancer. Specifically, we include the nonselective drug ketoconazole, and then the CYP17 targeted drugs abiraterone, orteronel (TAK-700), galaterone (TOK-001), and VT464. Using this framework, we can fully discriminate the clinical outcomes for ketoconazole, a drug with broad specificity, yet clinically ineffective, from that of abiraterone, the first CYP17 targeted therapy that is limited by its need for prednisone co-therapy. We also can identify potential next generation CYP17 targeted drugs now emerging that show signs of being far more 17,20 lyase selective. We conclude that a future for improved therapy without substantial cortisol decline, thus avoiding prednisone co-administration, seems possible at long last.

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

Cited by 14 publications

References 19 publications

Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency

Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency

Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated<b><i> CYP17A1</i></b> Alleles of Brazilian Patients

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

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