Dataset Information

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.

ABSTRACT: CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.

SUBMITTER: Boulanger G

PROVIDER: S-EPMC4539376 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.

Boulanger Gaella G Cibois Marie M Viet Justine J Fostier Alexis A Deschamps Stéphane S Pastezeur Sylvain S Massart Catherine C Gschloessl Bernhard B Gautier-Courteille Carole C Paillard Luc L

Molecular and cellular biology 20150713 18

CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression level ...[more]

PMID: 26169831

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Project description:BACKGROUND: Aromatase deficiency is a rare, autosomal recessive disorder of which there are approximately twenty four case reports. The aromatase enzyme is crucial in the biosynthesis of oestrogens from androgens. The phenotype of aromatase deficiency therefore is the result of androgen excess and oestrogen deficiency in the absence of normal aromatase activity. We report the first case of aromatase deficiency diagnosed in a female adult, at the age of 32 years, due to a novel duplication in the aromatase gene. CASE PRESENTATION: A 32 year old Indian woman presented with a history of gender assignment difficulties at birth, lack of pubertal development, osteopaenia with fracture and tall stature. She had central obesity, impaired fasting glucose and borderline hypertension. Past examinations had revealed partial fusion of urethra and vagina, hypoplastic uterus and streak ovaries. The ovaries had been excised due to malignant risk after an initial clinical diagnosis of Turner's syndrome with Y mosaicism. Oestrogen replacement commenced shortly after her fracture, in adulthood. After reassessment, aromatase deficiency was diagnosed. Sequencing of the coding exons of the aromatase (CYP19A1; OMIM 109710) gene revealed a novel 27-base duplication in exon 8 (p.Ala306_Ser314dup). This duplication, occurring within the aromatase ?-helix, would be likely to disrupt substrate (androgen) and cofactor (protoporphyrin IX) binding, resulting in a lack of oestrogen synthesis. CONCLUSIONS: We report a female with a phenotype compatible with aromatase deficiency which was unrecognised until adulthood and found she had a novel duplication in CYP19A1. Previous case reports have described polycystic ovarian morphology, especially in childhood and adolescence, but never streak ovaries. This may reflect the few adult cases reported, that aromatase deficiency in females is generally diagnosed at birth and oestrogen treatment commences decades earlier than occurred in our patient. Streak ovaries are consistent with the phenotype of the aromatase knockout mouse followed through adulthood. The observed clinical features of obesity, dysglycaemia and hypertension, are compatible with the observation that lack of a counterbalancing effect of oestrogen on tissue androgens until adulthood may lead to a metabolic syndrome phenotype. This report broadens the spectra of phenotype and genetic mutations underlying this rare disorder.

Dataset Information

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.

Publications

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.

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