title: X-linked adrenal hypoplasia congenita caused by a novel intronic mutation of the DAX-1 gene.
abstract: OBJECTIVE
  X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG) is caused by mutations of the DAX-1 gene. A novel intronic mutation of the gene and the results of in vitro expression analysis are reported.
  
  
  METHODS
  The patient is a 13-year-old boy who presented with severe dehydration and salt loss in the neonatal period, when he lacked cutaneous pigmentation and elevation of plasma ACTH level. He had been diagnosed and treated as adrenal hypoplasia. The DAX-1 gene was analyzed by direct DNA sequencing in the patient and his parents. In vitro expression analysis was applied to confirm the consequent missplicing of mRNA caused by the mutation.
  
  
  RESULTS
  The substitution of guanine for cytosine at the splice donor site (IVS1 + 1G>C) was observed in our patient and his mother. Expression analysis suggested that this mutation may hinder splicing of the adjacent intron and cause alternative activation of three cryptic splice donor sites within exon 1 leading to the aberrant splicing of mRNA and production of truncated proteins.
  
  
  CONCLUSIONS
  To our knowledge, this is the first case report of AHC associated with HHG caused by an intronic mutation of the DAX-1 gene. The clinical course of our patient may suggest that the onset of mineralocorticoid deficiency can precede that of glucocorticoid deficiency in some patients with AHC, and thus appear to suffer from aldosterone synthase deficiency at the onset of the disease.
authors.affiliation: Department of Pediatrics, Tokyo Metropolitan Hachioji Children's Hospital, Hachioji, Japan. mgoto@chp.hachioji.tokyo.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Goto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Katsumata
mesh_terms: D000293:Adolescent; D000307:Adrenal Gland Diseases / Q000235:genetics* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D009154:Mutation; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000324:Adrenocorticotropic Hormone