title: Mutations in CYP11B1 gene: phenotype-genotype correlations.
abstract: 11beta-hydroxylase deficiency, an autosomal recessive disorder, is the second most common cause of congenital adrenal hyperplasia. We studied four subjects with classic 11beta-hydroxylase deficiency and severe hypertension: a 46,XX affected subject from a Turkish family with severe ambiguity of the external genitalia and hypertension, and three affected 46,XY subjects from a Dominican kindred with isosexual precocious puberty and severe hypertension. The affected subjects had significantly elevated plasma 11-desoxycortisol, 11-desoxycorticosterone, Delta4-androstenedione, and testosterone. To determine the molecular genetic defects, genomic DNA was isolated from the leukocytes of affected subjects and their family members. The encoding region of the 11beta-hydroxylase gene (CYP11B1) was amplified by PCR with specific primers. Using single-stranded DNA conformational polymorphism (SSCP) and DNA sequencing, a nonsense mutation in exon 6 of CYP11B1 in the affected 46,XX subject from the Turkish family was identified, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 338 (Q338X). In the three 46,XY Dominican boys, the mutation was also a nonsense mutation in exon 6 of CYP11B1, where a cytosine was substituted by a thymidine, resulting in the replacement of glutamine (CAG) by a stop codon (TAG) at amino acid position 356 (Q356X). Both mutations result in the biosynthesis of a truncated 11beta-hydroxylase protein with loss of enzymatic activity. Heterozygosity was determined in family members of both probands including parents and siblings. These results indicate that mutations of CYP11B1 in these subjects are responsible for their clinical syndromes.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Yuan-Shan
authors.initials: YS
authors.lastname: Zhu
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cordero
authors.forename: Selcuk
authors.initials: S
authors.lastname: Can
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Cai
authors.forename: Xueke
authors.initials: X
authors.lastname: You
authors.forename: Cecilia
authors.initials: C
authors.lastname: Herrera
authors.forename: Mariano
authors.initials: M
authors.lastname: DeFillo-Ricart
authors.forename: Cedric
authors.initials: C
authors.lastname: Shackleton
authors.forename: Julianne
authors.initials: J
authors.lastname: Imperato-McGinley
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000235:genetics; D002675:Child, Preschool; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D004247:DNA; D013252:Steroid 11-beta-Hydroxylase