Aldosterone synthase deficiency caused by a homozygous L451F mutation in the CYP11B2 gene.
Isolated hypoaldosteronism is a rare cause of salt wasting in infancy and may be life-threatening, especially in the newborn infant. In a 3wk-old-boy with hyponatremia and hyperkalemia a GC-MS steroid profile on a spot urinary sample showed no 18-oxygenated steroid metabolites indicative for aldosterone synthase deficiency type I. Sequence analysis of the CYP11B2 gene revealed that the patient was homozygous for a novel missense mutation (L451F) caused by a T to C transition at position c.1351 in exon 8, whereas each non-symptomatic parent possessed only one mutated allele. The mutant cDNA was transiently expressed in a human cell line, HCT116 p53(-/-), and activity of the expressed protein optimized by co-expression of different adrenodoxin species, showing complete aldosterone deficiency with 11-deoxycorticosterone or corticosterone as substrates. The L451F mutation is the first mutation found located immediately adjacent to the highly conserved heme-binding C450 of the cytochrome P450. Computer modeling shows that replacement of leucine by phenylalanine leads to a steric effect in the immediate vicinity of the heme thereby preventing the activity of CYP11B2. Thus, by combining highly sensitive hormone detection in a spot urine sample with expression of the mutated cDNA in cell culture the phenotype of the patient can be correlated with a particular molecular defect.
Nguyen
Huy-Hoang
HH
Department of Biochemistry, Saarland University, D-66041 Saarbrücken, Germany.
Hannemann
Frank
F
Hartmann
Michaela F
MF
Wudy
Stefan A
SA
Bernhardt
Rita
R
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D019405:Cytochrome P-450 CYP11B2 / Q000172:deficiency* / Q000235:genetics*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D013256:Steroids / Q000652:urine
D013256:Steroids; D019405:Cytochrome P-450 CYP11B2; C033112:corticosterone methyl oxidase I