X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism caused by an inversion disrupting a conserved noncoding element upstream of the NR0B1 (DAX1) gene

J Clin Endocrinol Metab. 2009 Oct;94(10):4086-93. doi: 10.1210/jc.2009-0923. Epub 2009 Sep 22.

Abstract

Context: X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism (AHCH) is known to be caused by coding mutations in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene, encoding the transcriptional repressor dosage-sensitive sex-reversal adrenal hypoplasia critical region on the X chromosome protein 1 (DAX1).

Objective/patients: Four males in a family were affected by AHCH. Our aim was to locate the genetic cause of their disease, knowing that they had no mutation in the obvious candidate gene, NR0B1.

Design: Linkage analysis of the X chromosome and mutational screening of conserved noncoding regions upstream of NR0B1 were performed. To functionally characterize the genetic defect, studies of transcription and expression of DAX1 and steroidogenic factor 1 (SF-1) were done.

Results: A 60 Mb inversion on the X chromosome with one of the inversion breakpoints located in a conserved noncoding region 4 kb upstream of NR0B1 was detected. The inversion causes relocation of a putative SF-1 binding site implicated in murine gonadal development. A reporter construct lacking this enhancer element upstream of NR0B1 was unresponsive to SF-1 transcriptional activation. Immunohistochemistry suggested that the inversion leads to SF-1 silencing in the patients' testes both in childhood and in adult life.

Conclusion: We report a noncoding mutation causing AHCH, an inversion resulting in a phenotype similar to what is caused by intragenic NR0B1 null mutations. The inversion seems to disrupt and/or relocate regulatory sites crucial in DAX1 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Cortex / embryology
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adult
  • Child
  • Chromosome Inversion*
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics*
  • Female
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Linkage*
  • Humans
  • Hypogonadism / genetics*
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Male
  • Pedigree
  • Polymerase Chain Reaction
  • Receptors, Retinoic Acid / genetics*
  • Repressor Proteins / genetics*
  • Testis / embryology
  • Transcription, Genetic

Substances

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • NR0B1 protein, human
  • Receptors, Retinoic Acid
  • Repressor Proteins