Journal article

Publication year: 2008

Pages: 458-467

Journal: Molecular Genetics and Metabolism

Volume number: 93

Issue number: 4

ISSN: 1096-7192

eISSN: 1096-7206

DOI Link: https://doi.org/10.1016/j.ymgme.2007.11.009

Publisher: Elsevier

Abstract: 
Isolated hypoaldosteronism is a rare cause of salt wasting in infancy and may be life-threatening, especially in the newborn infant. In a 3 wk-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. (C) 2007 Elsevier Inc. All rights reserved.

Harvard Citation style: Nguyen, H., Hannemann, F., Hartmann, M., Wudy, S. and Bernhardt, R. (2008) Aldosterone synthase deficiency caused by L451F mutation in the CYP11B2 a homozygous gene, Molecular Genetics and Metabolism, 93(4), pp. 458-467. https://doi.org/10.1016/j.ymgme.2007.11.009

APA Citation style: Nguyen, H., Hannemann, F., Hartmann, M., Wudy, S., & Bernhardt, R. (2008). Aldosterone synthase deficiency caused by L451F mutation in the CYP11B2 a homozygous gene. Molecular Genetics and Metabolism. 93(4), 458-467. https://doi.org/10.1016/j.ymgme.2007.11.009