title: Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.
abstract: BACKGROUND
  Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens.
  
  
  OBJECTIVE
  To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.
  
  
  METHODS
  We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.
  
  
  METHODS
  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 COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type.
  
  
  CONCLUSIONS
  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 occurring in utero only.
authors.affiliation: Division of Endocrinology and Diabetology, University Children's Hospital ZürichDivision of Pediatrics, University Children's Hospital Zürich, Zürich, Switzerland.
authors.forename: Annik
authors.initials: A
authors.lastname: Hauri-Hohl
authors.forename: Monika
authors.initials: M
authors.lastname: Meyer-Böni
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Lang-Muritano
authors.forename: Mathias
authors.initials: M
authors.lastname: Hauri-Hohl
authors.forename: Eugen J
authors.initials: EJ
authors.lastname: Schoenle
authors.forename: Anna
authors.initials: A
authors.lastname: Biason-Lauber
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000473:pathology; D000328:Adult; D001141:Aromatase / Q000172:deficiency* / Q000235:genetics; D002648:Child; D005260:Female; D005838:Genotype; D006177:Gynecomastia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010641:Phenotype; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic
chemical_list: D001141:Aromatase; C561410:CYP19A1 protein, human