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


METHODS
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.


CONCLUSIONS
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.
Skinningsrud
Beate
B
Department of Medical Genetics, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway. beate.skinningsrud@medisin.uio.no
Husebye
Eystein S
ES
Gilfillan
Gregor D
GD
Frengen
Eirik
E
Erichsen
Aage
A
Gervin
Kristina
K
Ormerod
Eli
E
Egeland
Thore
T
Undlien
Dag E
DE
D000293:Adolescent; D000302:Adrenal Cortex / Q000196:embryology; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D002648:Child; D007446:Chromosome Inversion; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013737:Testis / Q000196:embryology; D014158:Transcription, Genetic
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins