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X-Linked Congenital Adrenal Hypoplasia with Hypogonadotropic Hypogonadism Caused by an Inversion Disrupting a Conserved Noncoding Element Upstream of the NR0B1 (DAX1) Gene

Department of Medical Genetics (B.S., G.D.G., K.G., E.O., D.E.U.), Oslo University Hospital, Ullevål, N-0407 Oslo, Norway; Institute of Medical Genetics (B.S., E.F., K.G., D.E.U.), University of Oslo, N-0315 Oslo, Norway; Section of Endocrinology (E.S.H.), Institute of Medicine, University of Bergen, N-5021 Bergen, Norway; Department of Medicine (E.S.H.), Haukeland University Hospital, N-5021 Bergen, Norway; Department of Pathology (A.E.), Oslo University Hospital, Ullevål, N-0407 Oslo, Norway; and Institute of Forensic Medicine (T.E.), University of Oslo, N-0027 Oslo, Norway

Address all correspondence and requests for reprints to: Beate Skinningsrud, Department of Medical Genetics, Oslo University Hospital, Ullevål, Kirkeveien 166, N-0407 Oslo, Norway. E-mail: beate.skinningsrud{at}medisin.uio.no.

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.