title: Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development.
abstract: OBJECTIVE
  Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD.
  
  
  METHODS
  Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum.
  
  
  METHODS
  Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected.
  
  
  RESULTS
  Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Müllerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism.
  
  
  CONCLUSIONS
  We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5-15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.
authors.affiliation: Institute of Experimental Paediatric Endocrinology, University Children's Hospital, Charité, Humboldt University, Berlin, Germany.
authors.forename: Sally
authors.initials: S
authors.lastname: Tantawy
authors.forename: Inas
authors.initials: I
authors.lastname: Mazen
authors.forename: Hala
authors.initials: H
authors.lastname: Soliman
authors.forename: Ghada
authors.initials: G
authors.lastname: Anwar
authors.forename: Abeer
authors.initials: A
authors.lastname: Atef
authors.forename: Mona
authors.initials: M
authors.lastname: El-Gammal
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Kotoury
authors.forename: Mona
authors.initials: M
authors.lastname: Mekkawy
authors.forename: Ahmad
authors.initials: A
authors.lastname: Torky
authors.forename: Agnes
authors.initials: A
authors.lastname: Rudolf
authors.forename: Pamela
authors.initials: P
authors.lastname: Schrumpf
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Dumargne
authors.forename: Rebekka
authors.initials: R
authors.lastname: Astudillo
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Birgit
authors.initials: B
authors.lastname: Köhler
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004534:Egypt; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007021:Hypospadias / Q000209:etiology; D007223:Infant; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C515057:NR5A1 protein, human; D011994:Recombinant Proteins; D054339:Steroidogenic Factor 1