title: Novel mutations of the SRD5A2 and AR genes in Thai patients with 46, XY disorders of sex development.
abstract: BACKGROUND
  Abnormalities of dihydrotestosterone conversion [5α-reductase deficiency: online Mendelian inheritance in man (OMIM) 607306] or actions of androgens [partial androgen insensitivity syndrome (PAIS): OMIM 312300] during the 8th-12th weeks of gestation cause varying degrees of undervirilized external genitalia in 46, XY disorders of sex development (DSD) with increased testosterone production. The objective of the study was to determine clinical and genetic characteristics of Thai patients with 46, XY DSD.
  
  
  METHODS
  A cross-sectional study was conducted in 46, XY DSD with increased testosterone production (n=43) evaluated by a human chorionic gonadotropin (hCG) stimulation test or clinical features consistent with 5α-reductase deficiency or PAIS. PCR sequencing of the entire coding regions of the SRD5A2 and AR genes was performed. Molecular modeling analysis of the androgen receptor-ligand-binding domain (AR-LBD) of a novel mutation was constructed.
  
  
  RESULTS
  Mutations were found in seven patients (16.3%): five (11.6%) and two (4.7%) patients had mutations in SRD5A2 and AR, respectively. Two novel mutations, SRD5A2 c.383A>G (p.Y128C) and AR c.2176C>T (p.R726C), were identified. Dimensional structural analysis of the novel mutated AR (p.R726C) revealed that it affected the co-activator binding [binding function-3 (BF-3)], not the testosterone binding site. Short phallus length was associated with 5α-reductase deficiency.
  
  
  CONCLUSIONS
  Around 16.3% of our patients with 46, XY DSD had 5α-reductase deficiency or PAIS. Two novel mutations of SRD5A2 and AR were identified. The novel mutated AR (p.R726C) might affect the co-activator binding (BF-3), not the testosterone binding site.
authors.forename: Chupong
authors.initials: C
authors.lastname: Ittiwut
authors.forename: Jaturong
authors.initials: J
authors.lastname: Pratuangdejkul
authors.forename: Vichit
authors.initials: V
authors.lastname: Supornsilchai
authors.forename: Sasipa
authors.initials: S
authors.lastname: Muensri
authors.forename: Yodporn
authors.initials: Y
authors.lastname: Hiranras
authors.forename: Taninee
authors.initials: T
authors.lastname: Sahakitrungruang
authors.forename: Suttipong
authors.initials: S
authors.lastname: Watcharasindhu
authors.forename: Kanya
authors.initials: K
authors.lastname: Suphapeetiporn
authors.forename: Vorasuk
authors.initials: V
authors.lastname: Shotelersuk
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000595:Amino Acid Sequence; D000728:Androgens / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D013196:Dihydrotestosterone / Q000378:metabolism; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013739:Testosterone / Q000378:metabolism; D013785:Thailand
chemical_list: C410798:AR protein, human; D000728:Androgens; D015415:Biomarkers; D008565:Membrane Proteins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human