The next 150 years of congenital adrenal hyperplasia

Turcu, Adina F.; Auchus, Richard J.

doi:10.1016/j.jsbmb.2015.05.013

Cited by 58 publications

(48 citation statements)

References 145 publications

(120 reference statements)

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“…); familial glucocorticoid deficiency (FGD) (caused by defects in STAR , MC2R , MRAP , MCM4 , NNT , TXNRD2 , GPX1 and PRDX3 ) (Miller ); and autoimmune disorders such as polyendocrinopathy syndrome type I, with or without reversible metaphyseal dysplasia (MIM# 240300, caused by defects in AIRE ) (Fig. ) (Miller and Auchus ; Turcu and Auchus ; Manna et al. ).…”

Section: Discussionmentioning

confidence: 99%

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency

Lara-Velazquez

Perdomo‐Pantoja

Blackburn

et al. 2017

Molec Gen & Gen Med

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BackgroundThe CYP11A1 gene encodes the cytochrome P450 side‐chain cleavage enzyme, which is essential for steroid formation. Recessive variants in this gene can lead to impairment of sexual differentiation caused by a complete or partial loss of steroid hormone production. The phenotypic spectrum in affected 46XY males may vary from surgically repairable defects including cryptorchidism and hypospadias to complete feminization of external gonads, accompanied by symptoms of adrenal dysfunction.MethodsWhole‐exome sequencing (WES) of a 12‐year‐old male proband and his parents was performed after a protracted diagnostic odyssey failed to uncover the cause of his primary adrenal insufficiency. Of note, the proband had early symptomatology and corrective surgery for hypospadias, raising suspicion for a disorder of steroidogenesis.Results WES identified compound heterozygous variants in CYP11A1 including a novel canonical splice site variant (c.425+1G>A) and a previously reported p.E314K variant, which were consistent with a diagnosis of congenital adrenal insufficiency with partial 46XY sex reversal.ConclusionCongenital adrenal insufficiency with 46XY sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G>A variant in trans with the p.E314K variant in CYP11A1. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site.

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Section: Discussionmentioning

confidence: 99%

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency

Lara-Velazquez

Perdomo‐Pantoja

Blackburn

et al. 2017

Molec Gen & Gen Med

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“…Steroid hormones are synthesized from cholesterol predominantly in the adrenal glands and gonads [1]. Dysfunction of these organs often cause deficiency in steroidogenesis, whereas patients suffer from painful and sometimes life-threatening conditions in the absence of hormone replacement [2][3][4][5][6]. Although hormone replacement therapy (HRT) well-established for treatment of these patients, the HRT is required throughout their life with the increased incidence of serious side effects.…”

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confidence: 99%

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

et al. 2016

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Abstract. Steroid hormones are mainly produced in adrenal glands and gonads. Because steroid hormones play vital roles in various physiological processes, replacement of deficient steroid hormones by hormone replacement therapy (HRT) is necessary for patients with adrenal and gonadal failure. In addition to HRT, tissue regeneration using stem cells is predicted to provide novel therapy. Among various stem cell types, mesenchymal stem cells can be differentiated into steroidogenic cells following ectopic expression of nuclear receptor (NR) 5A subfamily proteins, steroidogenic factor-1 (also known as adrenal 4 binding protein) and liver receptor homolog-1, with the aid of cAMP signaling. Conversely, these approaches cannot be applied to pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, because of poor survival following cytotoxic expression of NR5A subfamily proteins. However, if pluripotent stem cells are first differentiated through mesenchymal lineage, they can also be differentiated into steroidogenic cells via NR5A subfamily protein expression. This approach offers a potential suitable cells for future regenerative medicine and gene therapy for diseases caused by steroidogenesis deficiencies. It represents a powerful tool to investigate the molecular mechanisms involved in steroidogenesis. This article highlights our own and current research on the induction of steroidogenic cells from various stem cells. We also discuss the future direction of their clinical application.Key words: Steroid hormone, Steroidogenic factor-1/adrenal 4 binding protein, Liver receptor homolog-1, Stem cells, Transcription STEROID hormones play essential roles in various physiological processes, such as glucose metabolism, stress response, fluid and electrolyte balance, sex differentiation, reproduction and sexual behavior. Steroid hormones are synthesized from cholesterol predominantly in the adrenal glands and gonads [1]. Dysfunction of these organs often cause deficiency in steroidogenesis, whereas patients suffer from painful and sometimes life-threatening conditions in the absence of hormone replacement [2][3][4][5][6]. Although hormone replacement therapy (HRT) well-established for treatment of these patients, the HRT is required throughout their life with the increased incidence of serious side effects. It is hoped that stem cell-based regenerative medicine will provide novel therapies for resolving these issues. Stem cell-derived steroidogenic cells could restore the normal function of intrinsic organs following their transplantation. Consequently, induction of steroidogenic cells from stem cells represents an essential first-step in achieving this therapeutic goal. In addition, stem cell-derived steroidogenic cells provide a powerful tool to study the development and function of steroidogenic cells, because they reflect the intrinsic cell's developmental processes and characteristics. In this article, we describe our research and that of other groups for the induction of steroidogenic c...

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“…Epigenetic factors that lead to different phenotypes in nonclassic 21OHD patients with identical genotype have been suggested [59]. Intra-adrenal backdoor pathway metabolites might have physiological significance as paracrine/autocrine regulators of adrenocortical function through inhibition of P450 CYP17A1 [60].…”

Section: Perspectives Future Directions and Challengesmentioning

confidence: 99%

Human Adrenal Cortex: Epigenetics and Postnatal Functional Zonation

Baquedano¹,

Belgorosky²

2018

Horm Res Paediatr

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The human adrenal cortex, involved in adaptive responses to stress, fluid homeostasis, and secondary sexual characteristics, arises from a tightly regulated development of a zone and cell type-specific secretory pattern. However, the molecular mechanisms governing adrenal zonation, particularly postnatal zona reticularis development, which produce adrenal androgens in a lifetime-specific manner, remain poorly understood. Epigenetic events, including DNA and histone modifications as well as regulation by noncoding RNAs, are crucial in establishing or maintaining the expression pattern of specific genes and thus contribute to the stability of a specific differentiation state. Emerging evidence points to epigenetics as another regulatory layer that could contribute to establishing the adrenal zone-specific pattern of enzyme expression. Here, we outline the developmental milestones of the human adrenal cortex, focusing on current advances and understanding of epigenetic regulation of postnatal functional zonation. Numerous questions remain to be addressed emphasizing the need for additional investigations to elucidate the role of epigenetics in the human adrenal gland. Ultimately, improved understanding of the epigenetic factors involved in adrenal development and function could lead to novel therapeutic interventions.

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The next 150 years of congenital adrenal hyperplasia

Cited by 58 publications

References 145 publications

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

Human Adrenal Cortex: Epigenetics and Postnatal Functional Zonation

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