RGD Reference Report - Evidence for compromised aldosterone synthase enzyme activity in preeclampsia. - Rat Genome Database

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Evidence for compromised aldosterone synthase enzyme activity in preeclampsia.

Authors: Shojaati, K  Causevic, M  Kadereit, B  Dick, B  Imobersteg, J  Schneider, H  Beinder, E  Kashiwagi, M  Frey, BM  Frey, FJ  Mohaupt, MG 
Citation: Shojaati K, etal., Kidney Int. 2004 Dec;66(6):2322-8.
RGD ID: 1576428
Pubmed: PMID:15569322   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1523-1755.2004.66031.x   (Journal Full-text)

BACKGROUND: In normal pregnancy, an increased aldosterone (Aldo) concentration coincides with volume expansion. In preeclampsia, Aldo levels are low despite intravascular volume depletion. The present investigation aimed to characterize the compromised Aldo synthesis in preeclampsia, and to identify the molecular basis hereof. METHODS: We recruited 66 pregnant women (24 uneventful, 42 preeclamptic). Genomic DNA was isolated from peripheral blood leukocytes. Urine samples were obtained for gas chromatography-mass spectroscopic measurements of steroid hormones reflecting apparent Aldo synthase (CYP11B2) and 11-hydroxylase (CYP11B1) activities. Polymerase chain reaction (PCR)-based screening for CYP11B2 mutations was performed by SSCP, restriction analysis, and sequencing. RESULTS: CYP11B1 activity was unaltered, but reduction of mean tetrahydro (TH)-Aldo excretion by a factor of 3.9 indicated a diminished CYP11B2 activity in preeclampsia. Accordingly, the ratios of (TH-11-dehydrocorticosterone [A]+TH-corticosterone [B]+5alpha-THB) to (TH-cortisone +TH-cortisol [F]+5alpha-THF) and of 18-OH-THA to THAldo were increased in preeclampsia 2.6- and 15.2-fold, respectively, indicating reduced Aldo synthesis due to diminished methyl oxidase (MO) activity. A lower percentage of women with normal pregnancies had CYP11B2 mutations when compared to preeclamptic women (P < 0.05). Eight polymorphisms were detected, two of which were non-amino acid conserving. Of those, the mutation V386A, earlier found to jeopardize MO activity, was exclusively observed in preeclampsia (0% vs. 17%; P < 0.05). CONCLUSION: Aldo deficiency due to a compromised MO step of Aldo synthesis favors extracellular volume depletion, and may account for an increased risk of placental hypoperfusion and consecutive development of preeclampsia. The sole presence of mutation V386A in preeclamptic mothers may identify a subgroup with an increased risk to develop preeclampsia during pregnancy.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pre-eclampsia  IAGP 1576428DNA:missense mutation:cds:p.V386A (human)RGD 
pre-eclampsia  ISOCYP11B2 (Homo sapiens)1576428; 1576428DNA:missense mutation:cds:p.V386A (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp11b2  (cytochrome P450, family 11, subfamily b, polypeptide 2)

Genes (Mus musculus)
Cyp11b2  (cytochrome P450, family 11, subfamily b, polypeptide 2)

Genes (Homo sapiens)
CYP11B2  (cytochrome P450 family 11 subfamily B member 2)


Additional Information