title: Seven novel DAX1 mutations with loss of function identified in Chinese patients with congenital adrenal hypoplasia.
abstract: BACKGROUND
  DAX1 (for dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the X chromosome, gene 1; also called NROB1) mutations are responsible for adrenal failure and hypogonadotropic hypogonadism in patients with adrenal hypoplasia congenita (AHC), through a loss of trans-repression of SF-1 (for steroidogenic factor-1)-mediated StAR (for steroidogenic acute regulatory protein) and LHbeta transcriptional activities and a reduction of GnRH expression. The correlation of clinical features with genetic and functional alterations of the gene was investigated in detail in AHC patients.
  
  
  OBJECTIVE
  The present study aimed at identifying DAX1 mutations in Chinese AHC patients and investigating the functional defects of detected novel mutations.
  
  
  METHODS
  Nine patients with AHC were recruited from eight families. DAX1 mutations were screened, and the transcriptional activities of the identified mutations were assessed in vitro.
  
  
  RESULTS
  DAX1 mutations were detected in all nine patients enrolled in the study, with eight different mutations. Among the latter, seven are novel mutations, including two missense (L262P and C368F), one nonsense (Q222X), and four frame-shift (637delC, 652_653delAC, 973delC, and 774_775insCC) mutations. The functional studies showed that the mutant DAX1 was impaired by nuclear localization, loss of trans-repression of StAR and LHbeta transcriptional activities, and reduction of GnRH expression.
  
  
  CONCLUSIONS
  These findings provide insight into the molecular events by which DAX1 mutations influence the hypothalamus-pituitary-gonadal and hypothalamus-pituitary-adrenal axis and lead to AHC and hypogonadotropic hypogonadism.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Ruya
authors.initials: R
authors.lastname: Liu
authors.forename: Huijie
authors.initials: H
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Shouyue
authors.initials: S
authors.lastname: Sun
authors.forename: Manna
authors.initials: M
authors.lastname: Zhang
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yiming
authors.initials: Y
authors.lastname: Mu
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000150:complications / Q000151:congenital / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000151:congenital / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000502:physiology; D055815:Young Adult
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human