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Baquedano, M.S.; Ciaccio, M.; Marino, R.; Garrido, N.P.; Ramirez, P.; Maceiras, M.; Turjanski, A.; Defelipe, L.A.; Rivarola, M.A.; Belgorosky, A. "A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II" (2015) Journal of Clinical Endocrinology and Metabolism. 100(1):E191-E196
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Abstract:

Context: 3βHSD2 is a bifunctional microsomal NADβ-dependent enzyme crucial for adrenal and gonad steroid biosynthesis, convertingδ5-steroids toδ4-steroids. 3βHSD2 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 the 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 3βHSD2 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 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 NADβ-binding domain. Conclusions: 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. © 2015 by the Endocrine Society.

Registro:

Documento: Artículo
Título:A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II
Autor:Baquedano, M.S.; Ciaccio, M.; Marino, R.; Garrido, N.P.; Ramirez, P.; Maceiras, M.; Turjanski, A.; Defelipe, L.A.; Rivarola, M.A.; Belgorosky, A.
Filiación:Endocrine Service, Hospital de Pediatria Garrahan Ciudad Autonoma, Buenos Aires Pozos, 1881 (1245), Argentina
Hospital de Pediatria Garrahan CONICET, Buenos Aires, Argentina
Biological Chemistry Department, Instituto de Química Física de Los Materiales Medio Ambiente y Energia -CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:17 hydroxypregnenolone; androstenedione; glycine; nicotinamide adenine dinucleotide; prasterone; prasterone sulfate; pregnenolone; progesterone; renin; valine; 3 beta-hydroxysteroid dehydrogenase type II; 3beta hydroxy delta5 steroid dehydrogenase; amino acid substitution; Article; beta sheet; case report; cellular distribution; clitoromegaly; congenital adrenal hyperplasia; COS 7 cell line; DNA sequence; enzyme activity; female; gene; homozygosity; HSD3B2 gene; human; immunofluorescence test; in vitro study; infant; missense mutation; mutational analysis; progesterone synthesis; protein domain; protein expression; sequence analysis; structure activity relation; structure analysis; Western blotting; congenital adrenal hyperplasia; genetics; metabolism; precocious puberty; structure activity relation; Adrenal Hyperplasia, Congenital; Female; Humans; Infant; Mutation, Missense; Progesterone Reductase; Puberty, Precocious; Structure-Activity Relationship
Año:2015
Volumen:100
Número:1
Página de inicio:E191
Página de fin:E196
DOI: http://dx.doi.org/10.1210/jc.2014-2676
Título revista:Journal of Clinical Endocrinology and Metabolism
Título revista abreviado:J. Clin. Endocrinol. Metab.
ISSN:0021972X
CODEN:JCEMA
CAS:17 hydroxypregnenolone, 387-79-1; androstenedione, 26264-53-9, 63-05-8; glycine, 56-40-6, 6000-43-7, 6000-44-8; nicotinamide adenine dinucleotide, 53-84-9; prasterone, 53-43-0; prasterone sulfate, 651-48-9; pregnenolone, 145-13-1; progesterone, 57-83-0; renin, 61506-93-2, 9015-94-5; valine, 7004-03-7, 72-18-4; 3beta hydroxy delta5 steroid dehydrogenase, 9044-85-3; 3 beta-hydroxysteroid dehydrogenase type II; Progesterone Reductase
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0021972X_v100_n1_pE191_Baquedano

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Citas:

---------- APA ----------
Baquedano, M.S., Ciaccio, M., Marino, R., Garrido, N.P., Ramirez, P., Maceiras, M., Turjanski, A.,..., Belgorosky, A. (2015) . A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II. Journal of Clinical Endocrinology and Metabolism, 100(1), E191-E196.
http://dx.doi.org/10.1210/jc.2014-2676
---------- CHICAGO ----------
Baquedano, M.S., Ciaccio, M., Marino, R., Garrido, N.P., Ramirez, P., Maceiras, M., et al. "A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II" . Journal of Clinical Endocrinology and Metabolism 100, no. 1 (2015) : E191-E196.
http://dx.doi.org/10.1210/jc.2014-2676
---------- MLA ----------
Baquedano, M.S., Ciaccio, M., Marino, R., Garrido, N.P., Ramirez, P., Maceiras, M., et al. "A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II" . Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 1, 2015, pp. E191-E196.
http://dx.doi.org/10.1210/jc.2014-2676
---------- VANCOUVER ----------
Baquedano, M.S., Ciaccio, M., Marino, R., Garrido, N.P., Ramirez, P., Maceiras, M., et al. A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. New insight into the structurefunction relationships of 3βhydroxysteroid dehidrogenase type II. J. Clin. Endocrinol. Metab. 2015;100(1):E191-E196.
http://dx.doi.org/10.1210/jc.2014-2676