title: Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father.
abstract: OBJECTIVE
  To further investigate the molecular mechanism by which NR5A1/SF-1 mutation led to gonadal dysgenesis with predominant Sertoli cell defect.
  
  
  METHODS
  Genetic and functional mutation study.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Genetic analysis of an XY newborn with hypospadias and micropenis. Puberty developed spontaneously with a rise in T levels and normal LH contrasting with high FSH and low inhibin B concentrations, revealing a Sertoli cell defect.
  
  
  METHODS
  None.
  
  
  METHODS
  NR5A1/SF-1 gene molecular analysis.
  
  
  RESULTS
  Genetic analysis identified a new NR5A1/SF-1 mutation, c.842G>C (p.Arg281Pro). In vitro functional studies showed that the p.Arg281Pro mutant mainly altered Sertoli cell function, as observed in vivo with a high FSH level and low inhibin B concentration contrasting with normal LH concentration. The mutation was found in the father's DNA at a low copy number through direct sequencing and high-resolution melting assay, suggesting mosaicism.
  
  
  CONCLUSIONS
  We describe a new heterozygous NR5A1/SF-1 mutation that mainly altered Sertoli cell function. However, this 46,XY disorders of sex development (DSD) boy had no Müllerian derivatives, suggesting normal Sertoli cell function during fetal life. During puberty, Sertoli cell deficiency became more apparent. This is the first report of a progressive and predominant Sertoli cell defect in an XY patient with testicular dysgenesis owing to NR5A1/SF-1 mutation.
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU Montpellier et Université Montpellier I, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Philibert
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Ana
authors.initials: A
authors.lastname: Colmenares
authors.forename: Stephen
authors.initials: S
authors.lastname: Lortat-Jacob
authors.forename: Françoise
authors.initials: F
authors.lastname: Audran
authors.forename: Francis
authors.initials: F
authors.lastname: Poulat
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002452:Cell Count; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005220:Fathers; D006801:Humans; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D012708:Sertoli Cells / Q000473:pathology*; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1