title: Novel Heterozygous Mutations of NR5A1 and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency.
abstract: OBJECTIVE
  Heterozygous mutations of NR5A1, which encodes steroidogenic factor 1 (SF1), were identified in patients with 46,XY disorders of sex development (DSD) with normal adrenal function. This study was aimed to identify and functionally characterize mutations of NR5A1 in patients with 46,XY DSD.
  
  
  METHODS
  This study included 51 patients from 49 unrelated families with 46,XY DSD. Genomic DNA was extracted from peripheral blood leukocytes, and direct sequencing of all coding exons and their flanking introns of NR5A1 was performed. Transient transfections and dual-luciferase® reporter assays were performed to evaluate the effect of NR5A1 variants on transcriptional activity.
  
  
  RESULTS
  Four of 49 patients (8.2%) harbored a novel heterozygous sequence variant of NR5A1: c.80G>C (p.G26A), c.847T>C (p.C283R), c.1151del (p.L384Rfs*7), and c.1333G>T (p.E445*). They presented with female external genitalia with clitoromegaly in infancy or childhood, or primary amenorrhea in adolescence. In vitro functional studies of SF1 activity determined that each variant, except p.E445*, led to a reduced expression of downstream target genes and disturbed the regulation of gonadal development.
  
  
  CONCLUSIONS
  Loss-of-function mutations of NR5A1 are a relatively common cause of 46,XY DSD. Therefore, genetic defects of NR5A1 should be considered as an etiology in subjects with 46,XY DSD without adrenal insufficiency.
authors.affiliation: Genome Research Center for Birth Defects and Genetic Diseases, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyu Ha
authors.initials: KH
authors.lastname: Woo
authors.forename: Buwon
authors.initials: B
authors.lastname: Cheon
authors.forename: Ja Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jahyang
authors.initials: J
authors.lastname: Cho
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency; D000568:Amenorrhea / Q000209:etiology; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005091:Exons; D005260:Female; D005836:Genitalia, Female / Q000473:pathology; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011627:Puberty; D012741:Sexual Maturation / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1