CONTEXT: Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency (3β-HSDD) is caused by loss-of-function mutations in the HSD3B2 gene encoding type II 3β-HSD, which has a key role in steroid biosynthesis, converting Δ5-steroids to Δ4-steroids in adrenal glands and gonads. PATIENT: A patient (46, XX) was found to have elevated 17-hydroxyprogesterone (17-OHP) [203 nmol/l (normal range: 2·94 ± 0·9 nmol/l)] by newborn screening. Endocrinological examination revealed dramatically increased Δ5-steroids [e.g. 17-OH pregnenolone: 910 nmol/l (normal range: 12·6 ± 10·5 nmol/l)]. The patient had virilization of external genitalia with labial fusion, suggesting classical 3β-HSDD. METHODS AND RESULTS: Consistent with the endocrinological data, the patient was a compound heterozygote for two novel missense mutations (p.Y190C and p.S218P) that were identified in HSD3B2. Both Y190 and S218 are conserved among mammals. The mutant proteins had severely impaired residual enzymatic activity in vitro, although both mutants retained higher activity for 17-OH pregnenolone than for the other Δ5-steroids. In a three-dimensional model of the enzyme based on the known structures of similar proteins, both mutations were located extremely close to the predicted substrate-binding pocket. This suggests that the mutations can cause a local conformational change in the substrate-binding pocket, leading to alterations of the binding affinities for Δ5-steroids. CONCLUSIONS: We identified two novel missense mutations of HSD3B2 that resulted in unbalanced residual enzymatic activities for Δ5-steroids. As a potential novel mechanism, we propose that the mutations, which differently affect the activity towards different substrates, the effects of these mutations provide novel insights into the pathophysiology of 3β-HSDD.
CONTEXT: Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency (3β-HSDD) is caused by loss-of-function mutations in the HSD3B2 gene encoding type II 3β-HSD, which has a key role in steroid biosynthesis, converting Δ5-steroids to Δ4-steroids in adrenal glands and gonads. PATIENT: A patient (46, XX) was found to have elevated 17-hydroxyprogesterone (17-OHP) [203 nmol/l (normal range: 2·94 ± 0·9 nmol/l)] by newborn screening. Endocrinological examination revealed dramatically increased Δ5-steroids [e.g. 17-OH pregnenolone: 910 nmol/l (normal range: 12·6 ± 10·5 nmol/l)]. The patient had virilization of external genitalia with labial fusion, suggesting classical 3β-HSDD. METHODS AND RESULTS: Consistent with the endocrinological data, the patient was a compound heterozygote for two novel missense mutations (p.Y190C and p.S218P) that were identified in HSD3B2. Both Y190 and S218 are conserved among mammals. The mutant proteins had severely impaired residual enzymatic activity in vitro, although both mutants retained higher activity for 17-OH pregnenolone than for the other Δ5-steroids. In a three-dimensional model of the enzyme based on the known structures of similar proteins, both mutations were located extremely close to the predicted substrate-binding pocket. This suggests that the mutations can cause a local conformational change in the substrate-binding pocket, leading to alterations of the binding affinities for Δ5-steroids. CONCLUSIONS: We identified two novel missense mutations of HSD3B2 that resulted in unbalanced residual enzymatic activities for Δ5-steroids. As a potential novel mechanism, we propose that the mutations, which differently affect the activity towards different substrates, the effects of these mutations provide novel insights into the pathophysiology of 3β-HSDD.