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Aromatase deficiency due to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene


Hauri-Hohl, A; Meyer-Böni, M; Lang-Muritano, M; Hauri-Hohl, M; Schoenle, E J; Biason-Lauber, A (2011). Aromatase deficiency due to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene. Clinical Endocrinology, 75(1):39-43.

Abstract

Context  Aromatase deficiency in females is a rare 46,XX Disorder of Sex Differentiation characterized by a defect in catalyzing ooestrogens from androgens. Objective  To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analyzed their functional consequences. Design and Patient  We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy. Main Outcome Measurement  A genotype-phenotype correlation was found. Results  By direct sequencing of the CYP19A1 gene we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild type. Conclusion  Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occuring in utero only.

Abstract

Context  Aromatase deficiency in females is a rare 46,XX Disorder of Sex Differentiation characterized by a defect in catalyzing ooestrogens from androgens. Objective  To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analyzed their functional consequences. Design and Patient  We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy. Main Outcome Measurement  A genotype-phenotype correlation was found. Results  By direct sequencing of the CYP19A1 gene we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild type. Conclusion  Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occuring in utero only.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:25 Jan 2012 22:16
Last Modified:05 Apr 2016 15:24
Publisher:Wiley-Blackwell
ISSN:0300-0664
Publisher DOI:https://doi.org/10.1111/j.1365-2265.2011.04012.x
PubMed ID:21521281

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