A NOVEL MISSENSE MUTATION IN THE HSD3B2 GENE, UNDERLYING NONSALT-WASTING CONGENITAL ADRENAL HYPERPLASIA. NEW INSIGHT INTO THE STRUCTURE-FUNCTION RELATIONSHIPS OF 3- HYDROXYSTEROID DEHIDROGENASE TYPE II

BAQUEDANO S,; CIACCIO, M; MARINO R,; PEREZ G N,; RAMIREZ P; MACEIRAS M,; TURJANSKI A,; DEFELIPE L,; .RIVAROLA MA.,; BELGOROSKY A.

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2014

0021-972X

Context: 3HSD2 is a bifunctional microsomal NAD-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, converting5-steroids to4-steroids. 3HSD2 deficiency is a rare cause of congenital adrenal hyperplasia caused by recessive loss-of-function HSD3B2 mutations. Objective: The aim was to define the pathogenic consequences of a novel missense mutation in HSD3B2 gene. Patient: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 3HSD2 deficiency. Design and results: 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 6h, respectively). G250V-3HSD2 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 affect a L239-Q251 loop next to a -sheet structure in the NAD-binding domain.