title: HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism.
abstract: BACKGROUND
  Mutations in the transcription factor HESX1 have previously been described in association with septooptic dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis.
  
  
  OBJECTIVE
  Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism.
  
  
  METHODS
  Nonfamilial patients (724) with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities (n = 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents.
  
  
  METHODS
  All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects).
  
  
  RESULTS
  Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%.
  
  
  CONCLUSIONS
  Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis.
authors.affiliation: Biochemistry, Endocrinology, and Metabolism Unit, Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: David E G
authors.initials: DE
authors.lastname: McNay
authors.forename: James P
authors.initials: JP
authors.lastname: Turton
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Woods
authors.forename: Raja
authors.initials: R
authors.lastname: Brauner
authors.forename: Anastasios
authors.initials: A
authors.lastname: Papadimitriou
authors.forename: Eberhard
authors.initials: E
authors.lastname: Keller
authors.forename: Alexandra
authors.initials: A
authors.lastname: Keller
authors.forename: Nele
authors.initials: N
authors.lastname: Haufs
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Shalet
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D008423:Maternal Age; D008969:Molecular Sequence Data; D009900:Optic Nerve / Q000002:abnormalities; D010375:Pedigree; D010641:Phenotype; D010902:Pituitary Gland / Q000002:abnormalities; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D025962:Septo-Optic Dysplasia / Q000235:genetics* / Q000473:pathology
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins