title: Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations.
abstract: Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine disease. Steroid 11β-hydroxylase deficiency (11β-OHD) is the second most common form of CAH. The aim of the study was to study the functional consequences of three novel and one previously described CYP11B1 gene mutations (p.(Arg143Trp), p.(Ala306Val), p.(Glu310Lys) and p.(Arg332Gln)) detected in patients suffering from classical and non-classical 11β-OHD. Functional analyses were performed by using a HEK293 cell in vitro expression system comparing wild type (WT) with mutant 11β-hydroxylase activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein. Two mutations (p.(Ala306Val) and p.(Glu310Lys)) detected in patients with classical 11β-OHD showed a nearly complete loss of 11β-hydroxylase activity. The mutations p.(Arg143Trp) and p.(Arg332Gln) detected in patients with non-classical 11β-OHD showed a partial functional impairment with approximately 8% and 6% of WT activity, respectively. Functional mutation analysis allows the classification of novel CYP11B1 mutations as causes of classical and non-classical 11β-OHD. The detection of patients with non-classical phenotypes underscores the importance to screen patients with a phenotype comparable to non-classical 21-hydroxylase deficiency for mutations in the CYP11B1 gene in case of a negative analysis of the CYP21A2 gene. As CYP11B1 mutations are most often individual for a family, the in vitro analysis of novel mutations is essential for clinical and genetic counselling.
authors.affiliation: Program of Pediatric Endocrinology, Pediatric Unit, Department of Medical and Surgical Sciences; Azienda Policlinico S. Orsola Malpighi, University of Bologna, Bologna, Italy.
authors.forename: Soara
authors.initials: S
authors.lastname: Menabò
authors.affiliation: Erciyes University, Medical Faculty, Medical Genetics Department, Kayseri, Turkey.
authors.forename: Seher
authors.initials: S
authors.lastname: Polat
authors.affiliation: Program of Pediatric Endocrinology, Pediatric Unit, Department of Medical and Surgical Sciences; Azienda Policlinico S. Orsola Malpighi, University of Bologna, Bologna, Italy.
authors.forename: Lilia
authors.initials: L
authors.lastname: Baldazzi
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Kulle
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.affiliation: Biochemical Institute, Christian-Albrecht-University of Kiel, Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Endocrinology Unit - Department of Medical and Surgical Sciences; Center for Applied Biomedical Research (CRBA), Bologna, Italy.
authors.forename: Flaminia
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: Program of Pediatric Endocrinology, Pediatric Unit, Department of Medical and Surgical Sciences; Azienda Policlinico S. Orsola Malpighi, University of Bologna, Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Balsamo
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000097:blood / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D016415:Sequence Alignment; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D013252:Steroid 11-beta-Hydroxylase
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