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
CONTEXT: 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. OBJECTIVE: The aim...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_19457197_v100_n1_pE191_Baquedano |
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todo:paper_19457197_v100_n1_pE191_Baquedano2023-10-03T16:37:07Z 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 Baquedano, M.S. Ciaccio, M. Marino, R. Perez Garrido, N. Ramirez, P. Maceiras, M. Turjanski, A. Defelipe, L.A. Rivarola, M.A. Belgorosky, A. 3 beta-hydroxysteroid dehydrogenase type II 3beta hydroxy delta5 steroid dehydrogenase case report congenital adrenal hyperplasia female genetics human infant metabolism missense mutation precocious puberty structure activity relation Adrenal Hyperplasia, Congenital Female Humans Infant Mutation, Missense Progesterone Reductase Puberty, Precocious Structure-Activity Relationship CONTEXT: 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. 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 NAD+-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. Fil:Turjanski, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Defelipe, L.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_19457197_v100_n1_pE191_Baquedano |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
3 beta-hydroxysteroid dehydrogenase type II 3beta hydroxy delta5 steroid dehydrogenase case report congenital adrenal hyperplasia female genetics human infant metabolism missense mutation precocious puberty structure activity relation Adrenal Hyperplasia, Congenital Female Humans Infant Mutation, Missense Progesterone Reductase Puberty, Precocious Structure-Activity Relationship |
| spellingShingle |
3 beta-hydroxysteroid dehydrogenase type II 3beta hydroxy delta5 steroid dehydrogenase case report congenital adrenal hyperplasia female genetics human infant metabolism missense mutation precocious puberty structure activity relation Adrenal Hyperplasia, Congenital Female Humans Infant Mutation, Missense Progesterone Reductase Puberty, Precocious Structure-Activity Relationship Baquedano, M.S. Ciaccio, M. Marino, R. Perez Garrido, N. 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 structure-function relationships of 3β-hydroxysteroid dehidrogenase type II |
| topic_facet |
3 beta-hydroxysteroid dehydrogenase type II 3beta hydroxy delta5 steroid dehydrogenase case report congenital adrenal hyperplasia female genetics human infant metabolism missense mutation precocious puberty structure activity relation Adrenal Hyperplasia, Congenital Female Humans Infant Mutation, Missense Progesterone Reductase Puberty, Precocious Structure-Activity Relationship |
| description |
CONTEXT: 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. 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 NAD+-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. |
| format |
JOUR |
| author |
Baquedano, M.S. Ciaccio, M. Marino, R. Perez Garrido, N. Ramirez, P. Maceiras, M. Turjanski, A. Defelipe, L.A. Rivarola, M.A. Belgorosky, A. |
| author_facet |
Baquedano, M.S. Ciaccio, M. Marino, R. Perez Garrido, N. Ramirez, P. Maceiras, M. Turjanski, A. Defelipe, L.A. Rivarola, M.A. Belgorosky, A. |
| author_sort |
Baquedano, M.S. |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| url |
http://hdl.handle.net/20.500.12110/paper_19457197_v100_n1_pE191_Baquedano |
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