title: A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression.
abstract: OBJECTIVE
  NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms.
  
  
  METHODS
  We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localization and transactivation assays.
  
  
  RESULTS
  We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localization and impaired transcriptional activation without dominant-negative effects in both mutations.
  
  
  CONCLUSIONS
  We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Ayuko S
authors.initials: AS
authors.lastname: Suwanai
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.forename: Hidenori
authors.initials: H
authors.lastname: Haruna
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Yamataka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001008:Anxiety Disorders / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D003866:Depressive Disorder / Q000175:diagnosis / Q000235:genetics*; D012734:Disorders of Sex Development / Q000235:genetics*; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000175:diagnosis / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000175:diagnosis; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1