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

Coeli-Lacchini, Fernanda Borchers; Mermejo, Lívia Mara; Bodoni, Aline Faccioli; Elias, Lucila Leico Kagohara; Silva, Wilson A.; Antonini, Sonir Roberto Rauber; Moreira, Ayrton Custódio; Castro, Margaret de

doi:10.1055/a-1100-7066

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…described that more than 90% of patients with 17OHD received up to two incorrect diagnoses before the final diagnosis, confirming that 17OHD remains highly underdiagnosed ( 31 ). More than 130 mutations have been detected thus far, but W406R is the most prevalent in Brazil (50%), followed by R362C (approximately 30%) ( 32 – 34 ). HT starts during infancy and is difficult to control, predisposing patients to early renal and cardiovascular outcomes.…”

Section: Deoxycorticosterone As a Key Player ( Table 1 ...mentioning

confidence: 99%

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Costa-Barbosa¹,

Giorgi

Kater³

2022

Archives of Endocrinology and Metabolism

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High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.

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Section: Deoxycorticosterone As a Key Player ( Table 1 ...mentioning

confidence: 99%

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Costa-Barbosa¹,

Giorgi

Kater³

2022

Archives of Endocrinology and Metabolism

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“…Among these CAH forms, 17OHD is exceptionally rare, accounting for approximately 1% of all CAH cases with an incidence rate of approximately 1:50,000-100,000 [3]. Previous studies have demonstrated that mutations in cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), located on chromosome 10, contribute to the manifestation of 17OHD [4] and CYP17A1 consists of 508 amino acids, including eight exons and seven introns [5]. The gene encoding for cytochrome P450c17 ex-presses the activities of both 17α-hydroxylase and 17,20lyase [6].…”

Section: Introductionmentioning

confidence: 99%

Revealing a New Homozygous Variant in CYP17A1 c.908G>A (p. Gly303Asp) by Genotyping a Chinese Patient with 46, XY 17a-Hydroxylase/17,20-Lyase Deficiency and Adrenal Space-Occupying Lesion

Wang,

Hu,

et al. 2024

Discovery Medicine

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Background: 17α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). This study reports the case of a 22-year-old Chinese patient (46, XY) with 17OHD and a unilateral adrenal space-occupying lesion. Methods: The patient underwent serological, radiographic, genetic, and molecular analyses including whole-genome exome sequencing through high-throughput sequencing (HTS) technology to analyze the genetic conditions of both the patient and her parents. Additionally, chromosomal karyotype analysis was performed. The impact of the novel mutation on protein conformation was investigated by examining the three-dimensional structure of human CYP17A1 using the SWISS-MODEL website tool (PDB code 3RUK). Results: The patient had a chromosomal karyotype 46, XY, and presented with hypertension, hypokalemia, and male pseudohermaphroditism. Furthermore, decreased levels of testosterone, dehydroepiandrosterone sulfate, and estradiol, along with increased levels of progesterone, luteinizing hormone, and follicle-stimulating hormone (FSH), were observed. DNA sequencing revealed a homozygous mutation (c.908G>A, p.G303A) in the fifth exon of the CYP17A1. Both parents carried a heterozygous c.908G>A mutation in the same exon, confirming the inheritance of the patient's exonic mutation. Conclusion: For the first time, this study reports a novel homozygous mutation (c.908G>A in the fifth exon) in CYP17A1. Modeling analysis of CYP17A1 suggested that the substitution of glycine with aspartic acid at position 303 induces alterations in the number, structure, and electrostatic potential of the protein's local binding sites. The p.G303A mutation may possess pathogenic properties. Our study expands the mutation spectrum of CYP17A1.

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“…Mutations in CYP17A1 result in complete 17α-OHD or partial 17α-OHD [3]. The typical clinical manifestations of 17α-OHD are sexual naivety, with vague or feminine apparent de nition of the external genitalia; pubescent and adult females present with no pubertal development and primary amenorrhea, and males show vulval dysplasia or femininity [2,4]. Adrenocorticotropic hormone (ACTH) is compensated at a high level, which stimulates the excessive secretion of 11-deoxycorticosterone (11-DOC) and corticosterone (B), causing increased extracellular volume, hypokalaemia, and hypertension [2,5].…”

Section: Introductionmentioning

confidence: 99%

Novel mutations of the CYP17A1 gene cause disorders of sex development in two-chromosome karyotype 46,XY infants and a literature review: A case report

Dong,

Xi,

Cheng

et al. 2023

Preprint

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Background Congenital adrenal hyperplasia is a group of rare autosomal recessive diseases due to seven different enzyme mutations, and 17ɑ-hydroxylase deficiency is rare in congenital adrenal hyperplasia. The typical clinical manifestations of 17α-OHD are sexual naivety, with vague or feminine apparent definition of the external genitalia; pubescent and adult females present with no pubertal development and primary amenorrhea, and males show vulval dysplasia or femininity. Case presentation: The clinical features and laboratory and whole-exon sequencing test results were analysed in the 2 children with the chromosomal karyotype 46,XY 17ɑ-OHD at the ages of 2 months and 20 days (case 1) and 1 year and 2 months (case 2). Case 1 presented with cryptorchidism and a small penis with an external masculinization score of 7. Case 2 showed feminine external genitalia with a score of 4. Decreased morning cortisol levels, normal electrolytes and significantly increased luteinizing hormone and follicle-stimulating hormone were present in both cases. Both patients harboured compound heterozygous mutations in the CYP17A1 gene, and among them, had three novel mutations. Conclusions CYP17A1 gene defects in infants can manifest only as gonadal dysplasia and a lack of blood pressure and electrolyte abnormalities, which are easily misdiagnosed. Those with internal and/or external genitalia inconsistent with the chromosome karyotype should be alert to the possibility of 17ɑ-OHD. Adrenal steroid hormones and gene testing can be helpful for a definite diagnosis and early intervention.

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

Cited by 7 publications

References 37 publications

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Revealing a New Homozygous Variant in CYP17A1 c.908G>A (p. Gly303Asp) by Genotyping a Chinese Patient with 46, XY 17a-Hydroxylase/17,20-Lyase Deficiency and Adrenal Space-Occupying Lesion

Novel mutations of the CYP17A1 gene cause disorders of sex development in two-chromosome karyotype 46,XY infants and a literature review: A case report

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