• PMID: 19773398
• Gene Name: DAX1
• Condition: X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism
• Association: The study reports 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.
• Population size: 4
• Population details: 4 males with hypogonadotropic hypogonadism (AHCH)
• Sex: Male
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism

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

Skinningsrud B, Husebye ES, Gilfillan GD, Frengen E, Erichsen A, Gervin K, Ormerod E, Egeland T, Undlien DE.

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. FAU - Skinningsrud, Beate AU - Skinningsrud B AD - Department of Medical Genetics, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway. beate.skinningsrud@medisin.uio.no FAU - Husebye, Eystein S AU - Husebye ES FAU - Gilfillan, Gregor D AU - Gilfillan GD FAU - Frengen, Eirik AU - Frengen E FAU - Erichsen, Aage AU - Erichsen A FAU - Gervin, Kristina AU - Gervin K FAU - Ormerod, Eli AU - Ormerod E FAU - Egeland, Thore AU - Egeland T