PMID- 8538347
OWN - NLM
STAT- MEDLINE
DCOM- 19960208
LR  - 20190611
IS  - 0140-6736 (Print)
IS  - 0140-6736 (Linking)
VI  - 347
IP  - 8994
DP  - 1996 Jan 13
TI  - Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation 
      of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.
PG  - 88-91
AB  - BACKGROUND: 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the 
      interconversion of hormonally active cortisol to inactive cortisone and is vital 
      for dictating specificity for the mineralocorticoid receptor. Thus, in patients 
      with congenital deficiency of 11 beta-HSD (the syndrome of apparent 
      mineralocorticoid excess, AME), cortisol and not aldosterone acts as a 
      mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of 
      the renin-angiotensin-aldosterone axis. Two isoforms of human 11 beta-HSD have 
      been described, but it is the NAD-dependent type 2 isoform (11 beta-HSD2), first 
      characterised in placental tissue, that is expressed in the mineralocorticoid 
      target tissues, kidney and colon. We have analysed the 11 beta-HSD2 gene as a 
      candidate gene in explaining the molecular basis of AME. METHODS: By 
      exon-specific PCR-amplification of the 11 beta-HSD2 gene in a consanguineous 
      kindred with AME, we found a point mutation (C1228T) in two affected siblings, 
      and also in placental DNA obtained from a stillbirth pregnancy. FINDINGS: The 
      mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at 
      codon 374 instead of a normal arginine (R374X), with the deletion of 32 
      aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, 
      who are phenotypically normal, are heterozygote for the C1228T mutation in 
      keeping with an autosomal recessive form of inheritance. NAD-dependent 11 
      beta-HSD activity was severely attenuated in the stillbirth placenta compared 
      with control placental tissue, and no 11 beta-HSD immunostaining was observed in 
      this placenta with antisera derived against a C-terminal 11 beta-HSD2 peptide 
      sequence. INTERPRETATION: AME is due to a mutation in the 11 beta-HSD2 gene, and 
      is an example of human hypertension arising from a single gene defect.
FAU - Stewart, P M
AU  - Stewart PM
AD  - Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, 
      Edgbaston, UK.
FAU - Krozowski, Z S
AU  - Krozowski ZS
FAU - Gupta, A
AU  - Gupta A
FAU - Milford, D V
AU  - Milford DV
FAU - Howie, A J
AU  - Howie AJ
FAU - Sheppard, M C
AU  - Sheppard MC
FAU - Whorwood, C B
AU  - Whorwood CB
LA  - eng
SI  - GENBANK/S80133
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Mineralocorticoids)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenases)
SB  - IM
MH  - 11-beta-Hydroxysteroid Dehydrogenases
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Child
MH  - Female
MH  - Genotype
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/*genetics
MH  - Hypertension/*etiology
MH  - Infant
MH  - Male
MH  - Metabolism, Inborn Errors/complications/*genetics
MH  - Mineralocorticoids/blood
MH  - Molecular Sequence Data
MH  - Placenta/chemistry
MH  - *Point Mutation
MH  - Pregnancy
MH  - Syndrome
EDAT- 1996/01/13 00:00
MHDA- 1996/01/13 00:01
CRDT- 1996/01/13 00:00
PHST- 1996/01/13 00:00 [pubmed]
PHST- 1996/01/13 00:01 [medline]
PHST- 1996/01/13 00:00 [entrez]
AID - S0140-6736(96)90211-1 [pii]
AID - 10.1016/s0140-6736(96)90211-1 [doi]
PST - ppublish
SO  - Lancet. 1996 Jan 13;347(8994):88-91. doi: 10.1016/s0140-6736(96)90211-1.