A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. new insight into the structure-function relationships of 3β-hydroxysteroid dehidrogenase type II.

3βHSD2 is a bifunctional microsomal NAD+-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting Δ5-steroids to Δ4-steroids. 3βHSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by recessive loss-of-function HSD3B2 mutations.
The aim was to define the pathogenic consequences of a novel missense mutation in the HSD3B2 gene.
We report a 7-month-old 46,XX girl referred because of precocious pubarche and postnatal clitoromegaly. Hormonal profile showed inadequate glucocorticoid levels, increased 17OHP and renin levels, and very high DHEAS levels, suggestive of compensated nonsalt-losing 3βHSD2 deficiency.
Direct sequencing revealed a novel, homozygous, pG250V HSD3B2 mutation. In vitro analysis in intact COS-7 cells showed impaired enzymatic activity for the conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione (20% and 27% of WT at 6 h, respectively). G250V-3βHSD2 decreased the Vmax for progesterone synthesis without affecting the Km for pregnenolone. Western blot and immunofluorescence suggested that p.G250V mutation has no effect on the expression and intracellular localization of the mutant protein. Molecular homology modeling predicted that mutant V250 affected an L239-Q251 loop next to a β-sheet structure in the NAD+-binding domain.
We identified a novel p.G250V mutation of HSD3B2 which causes an incomplete loss of enzymatic activity, explaining the compensated nonsalt loss phenotype. In vitro and in silico experiments provided insight into the structure-function relationship of the 3βHSD2 protein suggesting the importance of the L239-Q251 loop for the catalytic activity of the otherwise stable 3βHSD2 enzyme.
AuthorsMaría Sonia Baquedano, Marta Ciaccio, Roxana Marino, Natalia Perez Garrido, Pablo Ramirez, Mercedes Maceiras, Adrian Turjanski, Lucas A Defelipe, Marco A Rivarola, Alicia Belgorosky
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 1 Pg. E191-6 (Jan 2015) ISSN: 1945-7197 [Electronic] United States
PMID25322271 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 3 beta-hydroxysteroid dehydrogenase type II
  • Progesterone Reductase
  • Adrenal Hyperplasia, Congenital (genetics, metabolism)
  • Female
  • Humans
  • Infant
  • Mutation, Missense
  • Progesterone Reductase (genetics, metabolism)
  • Puberty, Precocious (genetics, metabolism)
  • Structure-Activity Relationship

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