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Carboxyl-Terminal Mutations in 3β-Hydroxysteroid Dehydrogenase Type II Cause Severe Salt-Wasting Congenital Adrenal Hyperplasia

Maik Welzel, Nele Wüstemann, Gunter imi-Schleicher, Helmuth G. Dörr, Egbert Schulze, Guftar Shaikh, Peter Clayton, Joachim Grötzinger, Paul-Martin Holterhus and Felix G. Riepe

Division of Pediatric Endocrinology (M.W., N.W., P.-M.H., F.G.R.), Department of Pediatrics, Christian-Albrechts Universität zu Kiel, 24105 Kiel, Germany; Children’s Hospital of Bremen-Nord (G.S.-S.), 28755 Bremen, Germany; Division of Pediatric Endocrinology (H.G.D.), Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany; Laboratory of Molecular Genetics (E.S.), 69121 Heidelberg, Germany; University of Manchester (G.S., P.C.), Manchester M13 9PL, United Kingdom; and Institute of Biochemistry (J.G.), Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany

Address all correspondence and requests for reprints to: Felix G. Riepe, M.D., Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital Schleswig-Holstein, Schwanenweg 20, D-24105 Kiel, Germany. E-mail: friepe{at}pediatrics.uni-kiel.de.

Introduction: 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia caused by inactivating mutations in the HSD3B2 gene. Most mutations are located within domains regarded crucial for enzyme function. The function of the C terminus of the 3β-HSD protein is not known.

Objective: We studied the functional consequences of three novel C-terminal mutations in the 3β-HSD protein (p.P341L, p.R335X and p.W355X), detected in unrelated 46,XY neonates with classical 3β-HSD type II deficiency showing different degrees of under-virilization.

Methods and Results: In vitro expression of the two truncated mutant proteins yielded absent conversion of pregnenolone and dehydroepiandrosterone (DHEA), whereas the missense mutation p.P341L showed a residual DHEA conversion of 6% of wild-type activity. Additional analysis of p.P341L, including three-dimensional protein modeling, revealed that the mutant’s inactivity predominantly originates from a putative structural alteration of the 3β-HSD protein and is further aggravated by increased protein degradation. The stop mutations cause truncated proteins missing the final G-helix that abolishes enzymatic activity irrespective of an augmented protein degradation. Genital appearance did not correlate with the mutants’ residual in vitro activity.

Conclusions: Three novel C-terminal mutants of the HSD3B2 gene are responsible for classical 3β-HSD deficiency. The C terminus is essential for the enzymatic activity. However, more studies are needed to clarify the exact function of this part of the protein. Our results indicate that the genital phenotype in 3β-HSD deficiency cannot be predicted from in vitro 3β-HSD function alone.