title: A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17{alpha}-hydroxylase deficiency.
abstract: BACKGROUND
  17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported.
  
  
  OBJECTIVE
  A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient.
  
  
  RESULTS
  Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263G>A) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient.
  
  
  CONCLUSIONS
  This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 369 Zhizaoju Road, Shanghai 200011, People's Republic of China. qiaoj2001@126.com
authors.forename: Jie
authors.initials: J
authors.lastname: Qiao
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Bing-Li
authors.initials: BL
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Wu
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: He
authors.initials: H
authors.lastname: Jiang
authors.forename: Ting
authors.initials: T
authors.lastname: Gu
authors.forename: Bo-Ren
authors.initials: BR
authors.lastname: Jiang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Lu
authors.forename: Wan-Ling
authors.initials: WL
authors.lastname: Wu
authors.forename: Ming-Dao
authors.initials: MD
authors.lastname: Chen
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
mesh_terms: D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase