title: Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997.
abstract: We studied two of the three patients with a hereditary defect in the biosynthesis of aldosterone originally described by Visser and Cost in 1964. All three presented as newborns with salt-losing syndrome and failure to thrive. The original biochemical studies showed a defect in the 18-hydroxylation of corticosterone. According to the nomenclature proposed by Ulick, this defect would be termed corticosterone methyl oxidase deficiency type I. We measured plasma steroids in the untreated adult patients and performed molecular genetic studies. Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I. Cortisol and its precursors were in the normal range. Genetic defects in the gene CYP11B2 encoding aldosterone synthase (P450c11Aldo) have been described in a few cases. We identified a homozygous single base exchange (G to T) in codon 255 (GAG) causing a premature stop codon E255X (TAG). This mutation destroys a Aoc II restriction site. Digestion of a PCR fragment containing exon 4 of CYP11B2 (261 bp) with this restriction enzyme revealed in the two patients homozygous for the E255X mutation only a 261-bp fragment, whereas the heterozygous parents had three fragments (261 bp from the mutant allele and 194 and 67 bp from the wild-type allele). The mutant enzyme had lost the five terminal exons containing the heme binding site, and thus there was a loss of function enzyme. We conclude that the biochemical phenotype of these prismatic cases of congenital hypoaldosteronism can be explained by the patients genotype.
authors.affiliation: Department of Pediatrics, Christian-Albrechts-University of Kiel, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Peter
authors.forename: L
authors.initials: L
authors.lastname: Fawaz
authors.forename: S L
authors.initials: SL
authors.lastname: Drop
authors.forename: H K
authors.initials: HK
authors.lastname: Visser
authors.forename: W G
authors.initials: WG
authors.lastname: Sippell
mesh_terms: D015069:18-Hydroxycorticosterone / Q000097:blood; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis* / Q000097:blood; D001483:Base Sequence; D003345:Corticosterone / Q000097:blood; D019405:Cytochrome P-450 CYP11B2 / Q000172:deficiency* / Q000235:genetics; D004262:DNA Restriction Enzymes / Q000378:metabolism; D003900:Desoxycorticosterone / Q000097:blood; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: D003900:Desoxycorticosterone; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D019405:Cytochrome P-450 CYP11B2; D004262:DNA Restriction Enzymes; D003345:Corticosterone