Two homozygous mutations in the 11β-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess

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dc.contributor.authorCarvajal, CA
dc.contributor.authorGonzalez, AA
dc.contributor.authorRomero, DG
dc.contributor.authorGonzález, A
dc.contributor.authorMosso, LM
dc.contributor.authorLagos, ET
dc.contributor.authorHevia, MD
dc.contributor.authorRosati, MP
dc.contributor.authorPerez-Acle, TO
dc.contributor.authorGomez-Sanchez, CE
dc.contributor.authorMontero, JA
dc.contributor.authorFardella, CE
dc.date.accessioned2025-01-21T01:09:21Z
dc.date.available2025-01-21T01:09:21Z
dc.date.issued2003
dc.description.abstractThe human microsomal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) metabolizes active cortisol into cortisone and protects the mineralocorticoid receptor from glucocorticoid occupancy. In a congenital deficiency of 11beta-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia. In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene. This is a 4-yr-old male with arterial hypertension. The plasma renin activity and serum aldosterone were undetectable in the presence of a high cortisol to cortisone ratio. PCR amplification and sequence analysis of HSD11B2 gene showed the homozygous mutation in exon 4 Asp223Asn (GAC --> AAC) and a single nucleotide substitution C-->T in intron 3. Using site-directed mutagenesis, we generated a mutant 11betaHSD2 cDNA containing the Asp223Asn mutation. Wild-type and mutant cDNA was transfected into Chinese hamster ovary cells and enzymatic activities were measured using radiolabeled cortisol and thin-layer chromatography. The mRNA and 11betaHSD2 protein were detected by RT-PCR and Western blot, respectively. Wild-type and mutant 11betaHSD2 protein was expressed in Chinese hamster ovary cells, but the mutant enzyme had only 6% of wildtype activity. In silico 3D modeling showed that Asp223Asn changed the enzyme's surface electrostatic potential affecting the cofactor and substrate enzyme-binding capacity. The single substitution C-->T in intron 3 (IVS3 + 14 C-->T) have been previously reported that alters the normal splicing of pre-mRNA, given a nonfunctional protein. These findings may determine the full inactivation of this enzyme, explaining the biochemical profile and the early onset of hypertension seen in this patient.
dc.fuente.origenWOS
dc.identifier.doi10.1210/jc.2002-021909
dc.identifier.issn0021-972X
dc.identifier.urihttps://doi.org/10.1210/jc.2002-021909
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/96573
dc.identifier.wosidWOS:000183318200019
dc.issue.numero6
dc.language.isoen
dc.pagina.final2507
dc.pagina.inicio2501
dc.revistaJournal of clinical endocrinology & metabolism
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleTwo homozygous mutations in the 11β-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess
dc.typeartículo
dc.volumen88
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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