RGD Reference Report - Mutations in aldosterone synthase gene of Milan hypertensive rats: phenotypic consequences. - Rat Genome Database

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Mutations in aldosterone synthase gene of Milan hypertensive rats: phenotypic consequences.

Authors: Lloyd-MacGilp, SA  Torielli, L  Bechtel, S  Tripodi, G  Gomez-Sanchez, CE  Zagato, L  Bernhardt, R  Kenyon, CJ 
Citation: Lloyd-MacGilp SA, etal., Am J Physiol Endocrinol Metab 2002 Mar;282(3):E608-17.
RGD ID: 727991
Pubmed: PMID:11832364   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpendo.00043.2001   (Journal Full-text)

Using in vitro and in vivo methods, we have demonstrated increased sensitivity of adrenocortical steroidogenesis to ACTH in Milan hypertensive (MHS) compared with normotensive (MNS) rats and have investigated whether this is caused by mutations of steroidogenic enzymes. Genes encoding aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) in MHS and MNS have been cloned and sequenced. Nucleotide 752 (G) in exon 4 of MHS CYP11B2 differs from that of MNS (A); CYP11B1 sequences were identical. The nucleotide 752 mutation caused a Q251R substitution in the amino acid sequence of MHS CYP11B2. The phenotype of MHS CYP11B2 alleles, when expressed in COS-1 cells, differed from that of MNS alleles. The relative activities of the three reactions catalyzed by CYP11B2 (11beta-hydroxylation of deoxycorticosterone, 18-hydroxylation of corticosterone, and dehydrogenation of 18-hydroxycorticosterone) were estimated after incubation of transfected cells with [(14)C]deoxycorticosterone and analysis of radioactivity associated with deoxycorticosterone, corticosterone, 18 hydroxycorticosterone, and aldosterone. Both 11- and 18-hydroxylase activities were lower (19 and 12%, respectively; P < 0.01 and P < 0.05) in cells transfected with MHS compared with MNS alleles, whereas 18-oxidase activity was 42% higher (P < 0.01). To assess the significance of the CYP11B2 mutation in vivo, DNA from F2 hybrid MHS x MNS rats was genotyped. MHS alleles were associated with lower urine volumes in both sexes, lower ventricle weights in male rats, but no difference in systolic or diastolic blood pressures between the sexes. We conclude that a mutation in CYP11B2 may affect aldosterone secretion in MHS; however, under normal environmental circumstances, we were unable to demonstrate any influence of this mutation on blood pressure.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp11b2Rataldosterone biosynthetic process  IDA  RGD 
Cyp11b2RatC21-steroid hormone biosynthetic process  IDA  RGD 
Cyp11b2Ratglucocorticoid biosynthetic process  IDA corticosterone and 18-hydroxycorticosteroneRGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp11b2Ratcorticosterone 18-monooxygenase activity  IDA  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP11B2HumanC21-steroid hormone biosynthetic pathway  ISS  RGD 
Cyp11b2RatC21-steroid hormone biosynthetic pathway  IDA  RGD 
Cyp11b2MouseC21-steroid hormone biosynthetic pathway  ISS  RGD 
Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cyp11b2Ratabnormal adrenal gland morphology  IAGP  RGD 
Cyp11b2Ratdecreased heart left ventricle weight  IAGP  RGD 
Cyp11b2Ratincreased circulating aldosterone level  IAGP  RGD 
Cyp11b2Ratincreased circulating corticosterone level  IAGP  RGD 
Cyp11b2Ratsmall thymus  IAGP  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)

Objects referenced in this article
Gene Cyp11b2m1 cytochrome P450, family 11, subfamily b, polypeptide 2; mutation 1 Rattus norvegicus

Additional Information