A microdeletion within DAX-1 in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.
BACKGROUND
X-linked adrenal hypoplasia congenita (AHC) is a developmental disorder characterized by primary adrenal gland failure, which produces extreme and potentially fatal endocrine deficiencies. Hypogonadotrophic hypogonadism (HHG) also may be associated with AHC. AHC has been shown to result from a variety of mutations in the DAX-1 gene, which encodes a member of the nuclear hormone receptor superfamily.


METHODS
The proband, one of the world's oldest living patients with AHC and HHG, was diagnosed in 1955. He was on corticosteroid replacement therapy since that time and androgen replacement therapy since puberty. We sequenced his DAX-1 gene.


RESULTS
We found a 4 bp ACTC deletion between nucleotides 1464 and 1467 in the second exon of the normal DAX-1 sequence. This mutation caused a shift in the reading frame and predicted a premature stop codon at amino acid position 416. The mutation abolished a recognition site for DdeI, allowing for confirmation by restriction analysis.


CONCLUSIONS
The position of the mutation confirms the functional importance of the COOH-terminal 10% of the DAX-1 sequence. The clinical history also reinforces the importance of early diagnosis in AHC, which can be associated with longevity and no obvious morbidity after more than 40 years of hormone replacement therapy.
Wang
J
J
John P. Robarts Research Institute, London, Ontario, Canada.
Killinger
D W
DW
Hegele
R A
RA
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000312:Adrenal Hyperplasia, Congenital / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D017384:Sequence Deletion; D013739:Testosterone / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics*
D000305:Adrenal Cortex Hormones; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D013739:Testosterone; D004247:DNA