title: A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency.
abstract: BACKGROUND
  In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role.
  
  
  OBJECTIVE
  To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females.
  
  
  METHODS
  Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21-OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed.
  
  
  RESULTS
  The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females.
  
  
  CONCLUSIONS
  We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females.
authors.affiliation: Laboratx00F3;rio de Hormx00F4;nios e Genx00E9;tica Molecular - LIM/42, Unidade de Suprarrenal, Disciplina de Endocrinologia, Hospital das Clx00ED;nicas, Faculdade de Medicina, Universidade de Sx00E3;o Paulo, Sx00E3;o Paulo, Brazil.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kaupert
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Gomes
authors.forename: Vinícius N
authors.initials: VN
authors.lastname: Brito
authors.forename: Sofia H V
authors.initials: SH
authors.lastname: Lemos-Marini
authors.forename: Maricilda P
authors.initials: MP
authors.lastname: de Mello
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Longui
authors.forename: Cristiane
authors.initials: C
authors.lastname: Kochi
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Tânia A S S
authors.initials: TA
authors.lastname: Bachega
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000473:pathology; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000483:Alleles; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D014770:Virilism / Q000235:genetics* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human