title: Phenotypic and molecular characteristics in eleven Chinese patients with 5α-reductase Type 2 deficiency.
abstract: BACKGROUND
  Steroid 5α-reductase type 2 deficiency (5α-RD2) is a male-limited, autosomal recessive inherited disease. Affected 46, XY individuals usually present with ambiguous genitalia at birth. An early and precise diagnosis is of great value to the long-term prognosis of the disease.
  
  
  OBJECTIVE
  To describe the clinical features and molecular determinants in 11 Chinese patients with the SRD5A2 gene mutation and to investigate the functional alteration arising from a novel splicing site mutation identified in one of the patients.
  
  
  METHODS
  Eleven subjects born with abnormal external genitalia from 10 unrelated families were recruited. Among them, nine patients who were reared as girls underwent virilization and gender change after puberty. Genotyping analysis of the SRD5A2 gene was performed in each of the patients. Haplotype analysis was performed in five patients with a prevalent mutation of p.G203S to illustrate the founder effect in China. Functional impairment of the new variant was explored by an in vitro splicing study and enzymatic activity assay.
  
  
  RESULTS
  Nine mutations in the SRD5A2 gene were detected in the eleven patients. In addition to the previously reported p.G203S, p.R227Q, p.N193S, p.R246Q, p.Q6X, p.A228V, c.655delT and IVS1-2 A>G, a novel splicing site mutation (IVS4 + 2 T>C) was identified. From an in vitro functional study, this mutation was found to result in a skipping of exon 4 in the course of mRNA splicing, leading to a truncated protein of 205 amino acids that lacks the catalysing activity. Two siblings with the same compound heterozygous mutation (IVS1-2A>G/p.G203S) exhibited differing phenotypes and opposite patterns of gender rearing. A prevalent variation p.V89L combined with c.655delT was revealed to cause a mild phenotype of 5α-RD2 with a micropenis.
  
  
  CONCLUSIONS
  This cohort study describes the phenotypic, biochemical and long-term outcome in 11 Chinese patients with 5α-RD2 deficiency and defines the genotypic spectrum of SRD5A2 mutations in China.
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Mengxia
authors.initials: M
authors.lastname: Fan
authors.forename: Shuangxia
authors.initials: S
authors.lastname: Zhao
authors.forename: Haining
authors.initials: H
authors.lastname: Wang
authors.forename: Yingli
authors.initials: Y
authors.lastname: Lu
authors.forename: Chunming
authors.initials: C
authors.lastname: Pan
authors.forename: Fuguo
authors.initials: F
authors.lastname: Chen
authors.forename: Mingdao
authors.initials: M
authors.lastname: Chen
authors.forename: Huaidong
authors.initials: H
authors.lastname: Song
authors.forename: Kaixiang
authors.initials: K
authors.lastname: Cheng
authors.forename: Jie
authors.initials: J
authors.lastname: Qiao
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D000293:Adolescent; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D058490:Disorder of Sex Development, 46,XY / Q000208:ethnology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D022821:RNA Splice Sites; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human