title: Carboxyl-terminal mutations in 3beta-hydroxysteroid dehydrogenase type II cause severe salt-wasting congenital adrenal hyperplasia.
abstract: BACKGROUND
  3beta-Hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia caused by inactivating mutations in the HSD3B2 gene. Most mutations are located within domains regarded crucial for enzyme function. The function of the C terminus of the 3beta-HSD protein is not known.
  
  
  OBJECTIVE
  We studied the functional consequences of three novel C-terminal mutations in the 3beta-HSD protein (p.P341L, p.R335X and p.W355X), detected in unrelated 46,XY neonates with classical 3beta-HSD type II deficiency showing different degrees of under-virilization.
  
  
  RESULTS
  In vitro expression of the two truncated mutant proteins yielded absent conversion of pregnenolone and dehydroepiandrosterone (DHEA), whereas the missense mutation p.P341L showed a residual DHEA conversion of 6% of wild-type activity. Additional analysis of p.P341L, including three-dimensional protein modeling, revealed that the mutant's inactivity predominantly originates from a putative structural alteration of the 3beta-HSD protein and is further aggravated by increased protein degradation. The stop mutations cause truncated proteins missing the final G-helix that abolishes enzymatic activity irrespective of an augmented protein degradation. Genital appearance did not correlate with the mutants' residual in vitro activity.
  
  
  CONCLUSIONS
  Three novel C-terminal mutants of the HSD3B2 gene are responsible for classical 3beta-HSD deficiency. The C terminus is essential for the enzymatic activity. However, more studies are needed to clarify the exact function of this part of the protein. Our results indicate that the genital phenotype in 3beta-HSD deficiency cannot be predicted from in vitro 3beta-HSD function alone.
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts Universität zu Kiel, 24105 Kiel, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Welzel
authors.forename: Nele
authors.initials: N
authors.lastname: Wüstemann
authors.forename: Gunter
authors.initials: G
authors.lastname: Simic-Schleicher
authors.forename: Helmuth G
authors.initials: HG
authors.lastname: Dörr
authors.forename: Egbert
authors.initials: E
authors.lastname: Schulze
authors.forename: Guftar
authors.initials: G
authors.lastname: Shaikh
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation
chemical_list: D007527:Isoenzymes; D015096:3-Hydroxysteroid Dehydrogenases