* 124080

CYTOCHROME P450, SUBFAMILY XIB, POLYPEPTIDE 2; CYP11B2


Alternative titles; symbols

STEROID 11/18-BETA-HYDROXYLASE
STEROID 18-OXIDASE
ALDOSTERONE SYNTHASE; ALDOS


Other entities represented in this entry:

CORTICOSTERONE METHYLOXIDASE I, INCLUDED
CMO I, INCLUDED
CORTICOSTERONE METHYLOXIDASE II, INCLUDED
CMO II, INCLUDED
ALDOSTERONE TO RENIN RATIO, INCREASED, INCLUDED

HGNC Approved Gene Symbol: CYP11B2

Cytogenetic location: 8q24.3     Genomic coordinates (GRCh38): 8:142,910,559-142,917,843 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q24.3 {Low renin hypertension, susceptibility to} 3
Aldosterone to renin ratio raised 3
Hypoaldosteronism, congenital, due to CMO I deficiency 203400 AR 3
Hypoaldosteronism, congenital, due to CMO II deficiency 610600 AR 3

TEXT

Description

The CYP11B2 gene encodes a steroid 11/18-beta-hydroxylase (EC 1.14.15.5) that functions in mitochondria in the zona glomerulosa of the adrenal cortex to synthesize the mineralocorticoid aldosterone. The enzyme catalyzes all 3 necessary reactions: the 11-beta-hydroxylation of 11-deoxycorticosterone (11-DOC) to corticosterone (B); the 18-hydroxylation of corticosterone to 18-hydroxycorticosterone (18-OHB); and the 18-oxidation of 18-hydroxycorticosterone to aldosterone (Pascoe et al., 1992).

CYP11B2 shows high homology to the CYP11B1 gene (610613), which encodes a steroid 11-beta-hydroxylase. Both genes map to chromosome 8q21.


Cloning and Expression

In the course of cloning and analyzing the CYP11B1 gene, Mornet and White (1989) and Mornet et al. (1989) isolated a cross-hybridizing gene, symbolized CYP11B2. The deduced proteins share 93% sequence homology; both contain 503 amino acids, including a 24-residue mitochondrial signal peptide. Their 5-prime upstream regions are highly divergent, suggesting different regulation.

Kawainoto et al. (1990) isolated a cDNA corresponding to the CYP11B2 gene from an adrenal tumor of a patient with primary hyperaldosteronism. The deduced 503-amino acid protein catalyzed the formation of aldosterone from 11-deoxycorticosterone via corticosterone and 18-hydroxycorticosterone. A similar enzyme encoded by the CYP11B1 gene failed to catalyze the final reaction to form aldosterone.

Kawamoto et al. (1992) isolated the CYP11B2 gene from a human genomic DNA library. Studies in cultured cells demonstrated that the CYP11B2 and CYP11B1 enzymes catalyzed the 11-beta-hydroxylation of 11-deoxycorticosterone to form corticosterone. However, the CYP11B2 enzyme also showed steroid 18-hydroxylase activity, forming 18-hydroxycorticosterone and aldosterone, whereas the CYP11B1 enzyme did not catalyze the synthesis of aldosterone. Although the CYP11B2 gene product also showed some activity for glucocorticoids, Kawamoto et al. (1992) concluded that the main physiologic role of the enzyme is in mineralocorticoid production. The findings indicated that the 2 enzymes are products of 2 different genes and that the enzyme encoded by CYP11B1 participates in the synthesis of glucocorticoids, whereas the enzyme encoded by CYP11B2 participates in the synthesis of mineralocorticoids in humans.

In a series of cultured cell studies, Curnow et al. (1991) identified the CYP11B2 gene as that for the aldosterone-synthesizing enzyme in the zona glomerulosa of the adrenal gland. CYP11B2 mRNA levels were increased by physiologic levels of angiotensin II (see 106150).

Using RT-PCR, Kayes-Wandover and White (2000) found low expression of the CYP11B2 gene in fetal heart and adult aorta, but not in other regions of the adult heart. Levels of gene expression were typically 0.1% those in the adrenal gland, suggesting that aldosterone probably does not exert autocrine or paracrine effects in the normal adult human heart.


Gene Structure

Mornet and White (1989) determined that the CYP11B2 and CYP11B1 genes both contain 9 exons. The 8 introns are identical in location to the introns of CYP11A1 (118485), another mitochondrial P450 enzyme gene, confirming that all belong to the P450 superfamily.


Mapping

By use of somatic cell hybrid lines, Mornet and White (1989) mapped the CYP11B2 gene to chromosome 8q.

By radiation hybrid analysis, Taymans et al. (1998) mapped the CYP11B2 gene to the long arm of chromosome 8, proximal to the microsatellite polymorphic marker D8S1704. Fluorescence in situ hybridization refined the location to 8q24.3.


Gene Function

In in vitro studies using human adrenocortical cell lines, Clyne et al. (1997) demonstrated that CYP11B2 transcription was regulated by angiotensin II (160150) and potassium using the common cis elements cAMP response element (CRE) and steroidogenic factor-1 (SF1; 184757).

Condon et al. (2002) investigated the calcium-dependent mechanism regulating CYP11B2 transcription in a human adrenocortical cell line using a reporter construct containing the 5-prime region of the CYP11B2 gene. They found that CAMK (see CAMK1; 604998) and calmodulin (see CALM1; 114180) inhibitors blocked angiotensin II- and potassium-stimulated CYP11B2 reporter gene expression. CAMK1 augmented reporter expression when cellular calcium was elevated, but CAMK4 (114080) and CAMK2 (see 114078) had little or no effect. A constitutively active CAMK1 mutant stimulated reporter activity. Condon et al. (2002) concluded that CAMK1 is involved in angiotensin II- and potassium-stimulated CYP11B2 transcription.

In studies in rat cardiomyocytes, Tsybouleva et al. (2004) found that aldosterone increased expression of several hypertrophic markers via protein kinase D (PRKCM; 605435) and increased collagens and TGFB1 (190180) via PI3K-delta (PIK3CD; 602839). Inhibition of PRKCM and PIK3CD abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor antagonist spironolactone. In a mouse model of hypertrophic cardiomyopathy (CMH; see 192600), spironolactone reversed interstitial fibrosis, decreased myocyte disarray, and improved diastolic function. Tsybouleva et al. (2004) concluded that aldosterone is a major link between sarcomeric mutations and cardiac phenotype in CMH.


Molecular Genetics

Corticosterone Methyloxidase Type I Deficiency

In 3 Amish infants with corticosterone methyloxidase type I deficiency (CMO I; 203400) characterized by a defect in aldosterone synthesis and severe salt-wasting, Mitsuuchi et al. (1993) identified a homozygous mutation in the CYP11B2 gene (124080.0003). No enzyme was produced and the patients had complete absence of aldosterone.

Corticosterone Methyloxidase Type II Deficiency

In affected individuals from 7 Jewish Iranian families with corticosterone methyloxidase type II deficiency (610600), Pascoe et al. (1992) identified homozygosity for 2 mutations in the CYP11B2 gene: R181W and V386A (124080.0001). Eight asymptomatic individuals were homozygous for R181W alone and 3 asymptomatic individuals were homozygous for V386A alone, suggesting that both substitutions were necessary to cause the disorder. The families had previously been reported by Rosler et al. (1973, 1977), Cohen et al. (1977), and Globerman et al. (1988).

Glucocorticoid-Remediable Aldosteronism

In affected members of a family with glucocorticoid-remediable aldosteronism (GRA; 103900), clinically characterized by hypertension, variable hyperaldosteronism, and increased levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, Lifton et al. (1992) identified a chimeric gene in which the 5-prime regulatory sequences of the CYP11B1 gene were fused to the coding region of the CYP11B2 gene (610613.0002), resulting in ectopic expression of aldosterone synthase in the zona fasciculata. In Australian GRA patients, Miyahara et al. (1992) found that the chimeric gene encoded a fused P-450 protein consisting of the amino-terminal portion (exons 1-4) of CYP11B1 and the carboxyl-terminal part (exons 5-9) of CYP11B2.

Other Associations

Takeda et al. (1999) found increased aldosterone synthase activity and CYP11B2 mRNA expression in mononuclear leukocytes from 9 patients with idiopathic hyperaldosteronism compared to 10 patients with aldosterone-producing adenoma and 10 controls. No chimeric genes or mutations in the coding region of CYP11B2 were found in genomic DNA from these patients. Takeda et al. (1999) suggested that regulatory factors in the CYP11B2 gene may cause overexpression of CYP11B2 mRNA in patients with idiopathic hyperaldosteronism.

Mulatero et al. (2001) described severe hypertension due to paraneoplastic hyperaldosteronism in a 57-year-old man with non-Hodgkin lymphoma (605027). A test for the hybrid CYP11B1-CYP11B2 gene (610613.0002) was negative. Blood pressure returned to normal following chemotherapy, but it again increased as did plasma aldosterone concentrations when the lymphoma relapsed. The patient's lymph node sample showed increased expression of CYP11B2 mRNA. Primary aldosteronism associated with a malignant ovarian tumor has been reported (Todesco et al., 1975).

Tsybouleva et al. (2004) observed that myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4- to 6-fold in patients with hypertrophic cardiomyopathy compared to controls.

Lim et al. (2002) and Nicod et al. (2003) reported an association between 2 polymorphisms in the CYP11B2 gene (-344T-C, 124080.0010 and Int2C, 124080.0011) and an increased aldosterone-to-renin ratio (ARR) among patients with hypertension.

Ganapathipillai et al. (2005) identified 2 main haplotypes defined by SNPs in the CYP11B1 and CYP11B2 genes in independent populations from Europe and South America. The haplotypes consisted of 3 SNPs in the CYP11B2 gene, including -344C-T and Int2C, and 2 SNPs in the CYP11B1 gene. Among both populations, the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Urinary analysis of steroid metabolites showed an association between increased ARR and decreased 11-beta-hydroxylase activity, both associated with the TconvGTA haplotype. The authors concluded that genotypes at the CYP11B locus comprising both genes are in strong linkage disequilibrium and that certain haplotypes predict 11-beta-hydroxylase activity.


ALLELIC VARIANTS ( 13 Selected Examples):

.0001 CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, ARG181TRP AND VAL386ALA
  
RCV000018372...

In affected individuals from 7 Jewish Iranian families with corticosterone methyloxidase type II deficiency (610600), Pascoe et al. (1992) identified homozygosity for 2 mutations in the CYP11B2 gene: a C-to-T transition in exon 3, resulting in an arg181-to-trp (R181W) substitution, and a T-to-C transition in exon 7, resulting in a val386-to-ala (V386A) substitution. Eight asymptomatic individuals were homozygous for R181W alone and 3 asymptomatic individuals were homozygous for V386A alone, suggesting that both substitutions were necessary to cause the disorder. The families had previously been reported by Rosler et al. (1973, 1977), Cohen et al. (1977), and Globerman et al. (1988). In vitro functional expression studies showed that the R181W mutant enzyme had reduced 18-hydroxylase and undetectable 18-oxidase activities. The V386A substitution caused a small but consistent reduction in the production of 18-hydroxycorticosterone, reflecting some residual 18-hydroxylase activity.

See also Mitsuuchi et al. (1992).


.0002 CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, VAL386ALA AND GLU198ASP
  
RCV000018372...

In 2 French twins with isolated aldosterone synthase deficiency and a biochemical profile typical of CMO I deficiency (203400), Portrat-Doyen et al. (1998) identified homozygosity for 2 pathogenic changes in the CYP11B2 gene: val386-to-ala (V386A) and glu198-to-asp (E198D). Biochemical studies showed decreased aldosterone, decreased 18-OHB, and increased plasma renin, consistent with 18-hydroxylase deficiency. In vitro transfection assays showed that these substitutions individually had modest effects on the encoded enzyme, but when combined they resulted in decreased 11-beta-hydroxylase activity, a large decrease in 18-hydroxylase activity, and no detectable 18-oxidase activity. Portrat-Doyen et al. (1998) concluded that this disparity between the CYP11B2 enzyme with residual 18-hydroxylase activity, a trait more typical of CMO II deficiency (610600), and a biochemical phenotype typical of CMO I deficiency, suggested that phenotype-genotype relationships were not yet fully understood.


.0003 CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, 5-BP DEL
  
RCV000018374

In 3 patients with corticosterone methyloxidase type I deficiency (203400), Mitsuuchi et al. (1993) identified homozygosity for a 5-bp deletion in exon 1 of the CYP11B2 gene, resulting in a frameshift and premature termination of the protein. No enzyme was produced and the patients had complete absence of aldosterone synthesis. Nomoto et al. (1997) stated that the patients with the 5-bp deletion were Amish in origin.


.0004 REMOVED FROM DATABASE


.0005 CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, LEU461PRO
  
RCV000018375

In a Turkish patient with CMO I deficiency (203400), Nomoto et al. (1997) identified a homozygous T-to-C transition in exon 8 of the CYP11B2 gene, resulting in a leu461-to-pro (L461P) substitution. The mutation involved a putative heme binding site. In vitro functional expression studies showed that the L461P substitution totally abolished the 18-hydroxylase activity required for conversion of 11-deoxycorticosterone to aldosterone, even though the mutant product was detected in the mitochondrial fraction of the transfected cells.


.0006 CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, GLU255TER
  
RCV000018376...

In 2 Dutch patients with corticosterone methyloxidase type I deficiency (203400) originally reported by Visser and Cost (1964), Peter et al. (1997) identified a homozygous G-to-T transversion in exon 4 of the CYP11B2 gene, resulting in a glu255-to-ter (E255X) substitution. All 4 parents were heterozygous for the mutation; the family was consanguineous. The mutant enzyme was predicted to lack the 5 terminal exons that contain the heme binding site.

Williams et al. (2004) identified a patient who was compound heterozygous for E255X and a premature termination in codon 272 (124080.0013). The patient displayed a hormonal pattern intermediate between CMO types I and II (610600).


.0007 CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, THR185ILE
  
RCV000018377...

In a patient with CMO type II deficiency, Peter et al. (1998) demonstrated homozygosity for a C-to-T transition in the CYP11B2 gene, resulting in a thr185-to-ile (T185I) substitution. Both parents were heterozygous carriers for the mutation. The elevated ratio of 18-hydroxycorticosterone to aldosterone in the plasma was considered pathognomonic for CMO deficiency type II. The patient, born of consanguineous Hungarian gypsies, had originally been reported by Hauffa et al. (1991).

Dunlop et al. (2003) reported this mutation, which arises from a 554C-T transition, in an infant with CMO type II deficiency. This patient was compound heterozygous for T185I and a T498A substitution (124080.0012).


.0008 REMOVED FROM DATABASE


.0009 CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, 6-BP DUP, CODON 143
  
RCV000018378

In a patient with CMO type I deficiency (203400), Kayes-Wandover et al. (2001) identified a homozygous 6-bp duplication of 6 nucleotides (CGATTG) in exon 3 of the CYP11B2 gene, resulting in the insertion of 2 amino acids (arginine and leucine) at codon 143. In vitro functional expression studies showed that the mutant enzyme was completely inactive. The patient was unusual in that he presented at age 47 years after developing hyperkalemia in preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. He had increased serum renin with low serum and urinary levels of aldosterone and its metabolites, and normal or slightly elevated levels of 18-hydroxycorticosterone.


.0010 ALDOSTERONE TO RENIN RATIO, INCREASED

CYP11B2, -344C-T
  
RCV000018379

Lim et al. (2002) reported an association between a -344C-T polymorphism in the promoter region of the CYP11B2 gene and increased plasma aldosterone-to-renin ratio (ARR) among 326 patients with hypertension. The -344T-C polymorphism disrupts a putative steroidogenic factor-1 (SF1; 184757) binding site. The -344T-C polymorphism is in strong linkage disequilibrium with another polymorphism (Int2C; 124080.0011) in which intron 2 of the CYP11B2 gene is replaced with that from the neighboring CYP11B1 gene (610613). Lim et al. (2002) found significant excesses of -344T and intron 2 conversion alleles in patients with a raised ARR.

Among 141 hypertensive patients, Nicod et al. (2003) found increased frequency of the -344T and Int2C alleles in groups of patients with a high ARR (46% and 43%, respectively) compared to those with a normal ARR (22% and 17%; P less than 0.01 and P less than 0.005, respectively). Odds ratios for raised ARR in subjects with a homozygous -344T and Int2 C haplotype were 6.1 (95% CI, 1.6-22.5; P less than 0.005) when compared with the contrasting haplotype. Linear modeling of individual postural changes in renin and aldosterone showed a maximal achievable aldosterone increase of 110 pmol/liter with no mutated haplotype and 500 pmol/liter with 2 mutated haplotypes. These findings supported the view of a molecular basis regulating aldosterone production.

Mulatero et al. (2006) studied the role of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) and of genes involved in sodium handling on blood pressure in acromegaly (102200). Patients with the CYP11B2 -344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4-11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 -344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Mulatero et al. (2006) concluded that there is an association of the -344T/C CYP11B2 gene polymorphism with blood pressure in patients with acromegaly.


.0011 ALDOSTERONE TO RENIN RATIO, INCREASED

CYP11B2, IVS2 CONVERSION
   RCV000018380

This variant in the CYP11B2 gene is a polymorphic variant that reflects replacement of the intron 2 from CYP11B2 with that from the neighboring CYP11B1 gene (610613). It is referred to as 'Int2C' for 'intron 2 conversion.'

Lim et al. (2002) and Nicod et al. (2003) reported an increased frequency of the intron 2 conversion allele in hypertensive patients with increased aldosterone-to-renin ratios (see 124080.0010).


.0012 CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, THR498ALA
  
RCV000018381...

In an infant with CMO type II deficiency (610600), Dunlop et al. (2003) identified compound heterozygosity for 2 mutations in the CYP11B2 gene: a 1492A-G transition in exon 9, resulting in a thr498-to-ala (T498A) substitution, and T185I (124080.0007). The infant had failure to thrive, persistent hyponatremia, and episodic vomiting and diarrhea. Each unaffected parent was heterozygous for 1 of the mutations. Functional expression studies in COS cells showed steroidogenic patterns typical of CMO type II deficiency, including very low levels of aldosterone synthesis (0.5% or less of wildtype enzyme) consistent with the low aldosterone levels in the patient's plasma. Both mutations localized to the beta-3-sheet in the cytochrome P450 enzyme structure, as does the R181W mutation (124080.0001). Mutations in this region suggest that is important for conferring the unique ability of aldosterone synthase to catalyze efficient oxygenation of the C18 carbon of steroid substrates.


.0013 CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, GLU272TER
  
RCV000018382

Williams et al. (2004) studied a 4-week-old child of unrelated parents for failure to thrive and salt-wasting with hyperkalemia, high plasma renin, and low-normal aldosterone levels. Urinary metabolite ratios of corticosterone/18-hydroxycorticosterone and 18-hydroxycorticosterone/aldosterone were intermediate between CMO types I (203400) and II (610600). Sequence analysis of the CYP11B2 gene showed that the patient was a compound heterozygote for a previously described E255X mutation (124080.0006) and a glu272-to-ter (Q272X) mutation that arose from a C-to-T transition in exon 5. The patient's unaffected father and mother were heterozygous for the E255X and Q272X mutations, respectively. Thus, the patient had 2 truncated forms of aldosterone synthase predicted to be inactive because they lacked critical active site residues as well as the heme-binding site. This case of CMO was considered of particular interest because despite the apparent lack of aldosterone synthase activity, the patient displayed low-normal aldosterone levels, thus raising the question of its source.


See Also:

REFERENCES

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  25. Pascoe, L., Curnow, K. M., Slutsker, L., Rosler, A., White, P. C. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc. Nat. Acad. Sci. 89: 4996-5000, 1992. [PubMed: 1594605, related citations] [Full Text]

  26. Peter, M., Bunger, K., Solyom, J., Sippell, W. G. Mutation thr185-to-ile is associated with corticosterone methyl oxidase deficiency type II. Europ. J. Pediat. 157: 378-381, 1998. [PubMed: 9625333, related citations] [Full Text]

  27. Peter, M., Fawaz, L., Drop, S. L. S., Visser, H. K. A., Sippell, W. G. Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997. J. Clin. Endocr. Metab. 82: 3525-3528, 1997. [PubMed: 9360501, related citations] [Full Text]

  28. Portrat-Doyen, S., Tourniaire, J., Richard, O., Mulatero, P., Aupetit-Faisant, B., Curnow, K. M., Pascoe, L., Morel, Y. Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene. J. Clin. Endocr. Metab. 83: 4156-4161, 1998. [PubMed: 9814506, related citations] [Full Text]

  29. Rosler, A., Rabinowitz, D., Theodor, R., Ramirez, L. C., Ulick, S. Nature of defect in a salt-wasting disorder in Jews in Iran. J. Clin. Endocr. Metab. 44: 279-291, 1977. [PubMed: 838841, related citations] [Full Text]

  30. Rosler, A., Theodor, R., Gazit, E., Biochis, H., Rabinowitz, D. Salt wasting, raised plasma-renin activity, and normal or high plasma-aldosterone: a form of pseudohypoaldosteronism. Lancet 301: 959-962, 1973. Note: Originally Volume 1. [PubMed: 4121586, related citations] [Full Text]

  31. Takeda, Y., Furukawa, K., Inaba, S., Miyamori, I., Mabuchi, H. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J. Clin. Endocr. Metab. 84: 1633-1637, 1999. [PubMed: 10323392, related citations] [Full Text]

  32. Taymans, S. E., Pack, S., Pak, E., Torpy, D. J., Zhuang, Z., Stratakis, C. A. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J. Clin. Endocr. Metab. 83: 1033-1036, 1998. [PubMed: 9506770, related citations] [Full Text]

  33. Todesco, S., Terribile, V., Borsatti, A., Mantero, F. Primary aldosteronism due to a malignant ovarian tumor. J. Clin. Endocr. Metab. 41: 809-819, 1975. [PubMed: 171276, related citations] [Full Text]

  34. Tsybouleva, N., Zhang, L., Chen, S., Patel, R., Lutucuta, S., Nemoto, S., DeFreitas, G., Entman, M., Carabello, B. A., Roberts, R., Marian, A. J. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and cardiac phenotype of hypertrophic cardiomyopathy. Circulation 109: 1284-1291, 2004. [PubMed: 14993121, images, related citations] [Full Text]

  35. Visser, H. K. A., Cost, W. S. A new hereditary defect in the biosynthesis of aldosterone: urinary C(21)-corticosteroid pattern in three related patients with a salt-losing syndrome, suggesting an 18-oxidation defect. Acta Endocr. 47: 589-612, 1964. [PubMed: 14250395, related citations] [Full Text]

  36. Williams, T. A., Mulatero, P., Bosio, M., Lewicka, S., Palermo, M., Veglio, F., Armanini, D. A particular phenotype in a girl with aldosterone synthase deficiency. J. Clin. Endocr. Metab. 89: 3168-3172, 2004. [PubMed: 15240589, related citations] [Full Text]


John A. Phillips, III - updated : 9/28/2007
Cassandra L. Kniffin - reorganized : 12/13/2006
Cassandra L. Kniffin - updated : 12/6/2006
John A. Phillips, III - updated : 10/20/2006
John A. Phillips, III - updated : 5/18/2006
Patricia A. Hartz - updated : 2/9/2006
Marla J. F. O'Neill - updated : 1/18/2006
John A. Phillips, III - updated : 2/5/2004
John A. Phillips, III - updated : 1/10/2003
John A. Phillips, III - updated : 2/26/2002
John A. Phillips, III - updated : 7/11/2001
Victor A. McKusick - updated : 6/1/2001
John A. Phillips, III - updated : 3/5/2001
John A. Phillips, III - updated : 3/20/2000
John A. Phillips, III - updated : 3/18/1999
Victor A. McKusick - updated : 8/26/1998
John A. Phillips, III - updated : 6/24/1998
John A. Phillips, III - updated : 1/3/1998
Victor A. McKusick - edited : 12/11/1997
Victor A. McKusick - updated : 6/17/1997
John A. Phillips, III - updated : 12/20/1996
Creation Date:
Victor A. McKusick : 6/6/1989
carol : 09/18/2013
terry : 4/29/2009
alopez : 9/28/2007
carol : 12/13/2006
ckniffin : 12/6/2006
alopez : 10/20/2006
wwang : 6/22/2006
alopez : 5/18/2006
mgross : 3/7/2006
terry : 2/9/2006
wwang : 1/18/2006
wwang : 12/13/2005
joanna : 12/6/2005
terry : 5/4/2005
terry : 4/28/2005
carol : 3/17/2004
tkritzer : 2/6/2004
alopez : 2/5/2004
tkritzer : 11/13/2003
tkritzer : 11/10/2003
terry : 11/6/2003
alopez : 10/2/2003
alopez : 1/10/2003
alopez : 6/11/2002
alopez : 6/11/2002
alopez : 2/26/2002
alopez : 2/26/2002
alopez : 7/11/2001
mcapotos : 6/6/2001
mcapotos : 6/5/2001
terry : 6/1/2001
mgross : 3/5/2001
mgross : 3/31/2000
mgross : 3/27/2000
terry : 3/20/2000
mgross : 3/23/1999
mgross : 3/18/1999
mgross : 3/18/1999
carol : 11/25/1998
carol : 9/1/1998
terry : 8/26/1998
dholmes : 6/29/1998
dholmes : 6/24/1998
alopez : 1/26/1998
alopez : 1/26/1998
mark : 12/17/1997
terry : 12/11/1997
terry : 9/8/1997
terry : 9/3/1997
alopez : 6/20/1997
alopez : 6/17/1997
jenny : 5/27/1997
jenny : 5/21/1997
jenny : 5/21/1997
terry : 5/24/1996
terry : 10/12/1994
mimadm : 6/25/1994
warfield : 4/8/1994
carol : 3/22/1993
carol : 3/20/1993
carol : 7/8/1992

* 124080

CYTOCHROME P450, SUBFAMILY XIB, POLYPEPTIDE 2; CYP11B2


Alternative titles; symbols

STEROID 11/18-BETA-HYDROXYLASE
STEROID 18-OXIDASE
ALDOSTERONE SYNTHASE; ALDOS


Other entities represented in this entry:

CORTICOSTERONE METHYLOXIDASE I, INCLUDED
CMO I, INCLUDED
CORTICOSTERONE METHYLOXIDASE II, INCLUDED
CMO II, INCLUDED
ALDOSTERONE TO RENIN RATIO, INCREASED, INCLUDED

HGNC Approved Gene Symbol: CYP11B2

SNOMEDCT: 47757001;  


Cytogenetic location: 8q24.3     Genomic coordinates (GRCh38): 8:142,910,559-142,917,843 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8q24.3 {Low renin hypertension, susceptibility to} 3
Aldosterone to renin ratio raised 3
Hypoaldosteronism, congenital, due to CMO I deficiency 203400 Autosomal recessive 3
Hypoaldosteronism, congenital, due to CMO II deficiency 610600 Autosomal recessive 3

TEXT

Description

The CYP11B2 gene encodes a steroid 11/18-beta-hydroxylase (EC 1.14.15.5) that functions in mitochondria in the zona glomerulosa of the adrenal cortex to synthesize the mineralocorticoid aldosterone. The enzyme catalyzes all 3 necessary reactions: the 11-beta-hydroxylation of 11-deoxycorticosterone (11-DOC) to corticosterone (B); the 18-hydroxylation of corticosterone to 18-hydroxycorticosterone (18-OHB); and the 18-oxidation of 18-hydroxycorticosterone to aldosterone (Pascoe et al., 1992).

CYP11B2 shows high homology to the CYP11B1 gene (610613), which encodes a steroid 11-beta-hydroxylase. Both genes map to chromosome 8q21.


Cloning and Expression

In the course of cloning and analyzing the CYP11B1 gene, Mornet and White (1989) and Mornet et al. (1989) isolated a cross-hybridizing gene, symbolized CYP11B2. The deduced proteins share 93% sequence homology; both contain 503 amino acids, including a 24-residue mitochondrial signal peptide. Their 5-prime upstream regions are highly divergent, suggesting different regulation.

Kawainoto et al. (1990) isolated a cDNA corresponding to the CYP11B2 gene from an adrenal tumor of a patient with primary hyperaldosteronism. The deduced 503-amino acid protein catalyzed the formation of aldosterone from 11-deoxycorticosterone via corticosterone and 18-hydroxycorticosterone. A similar enzyme encoded by the CYP11B1 gene failed to catalyze the final reaction to form aldosterone.

Kawamoto et al. (1992) isolated the CYP11B2 gene from a human genomic DNA library. Studies in cultured cells demonstrated that the CYP11B2 and CYP11B1 enzymes catalyzed the 11-beta-hydroxylation of 11-deoxycorticosterone to form corticosterone. However, the CYP11B2 enzyme also showed steroid 18-hydroxylase activity, forming 18-hydroxycorticosterone and aldosterone, whereas the CYP11B1 enzyme did not catalyze the synthesis of aldosterone. Although the CYP11B2 gene product also showed some activity for glucocorticoids, Kawamoto et al. (1992) concluded that the main physiologic role of the enzyme is in mineralocorticoid production. The findings indicated that the 2 enzymes are products of 2 different genes and that the enzyme encoded by CYP11B1 participates in the synthesis of glucocorticoids, whereas the enzyme encoded by CYP11B2 participates in the synthesis of mineralocorticoids in humans.

In a series of cultured cell studies, Curnow et al. (1991) identified the CYP11B2 gene as that for the aldosterone-synthesizing enzyme in the zona glomerulosa of the adrenal gland. CYP11B2 mRNA levels were increased by physiologic levels of angiotensin II (see 106150).

Using RT-PCR, Kayes-Wandover and White (2000) found low expression of the CYP11B2 gene in fetal heart and adult aorta, but not in other regions of the adult heart. Levels of gene expression were typically 0.1% those in the adrenal gland, suggesting that aldosterone probably does not exert autocrine or paracrine effects in the normal adult human heart.


Gene Structure

Mornet and White (1989) determined that the CYP11B2 and CYP11B1 genes both contain 9 exons. The 8 introns are identical in location to the introns of CYP11A1 (118485), another mitochondrial P450 enzyme gene, confirming that all belong to the P450 superfamily.


Mapping

By use of somatic cell hybrid lines, Mornet and White (1989) mapped the CYP11B2 gene to chromosome 8q.

By radiation hybrid analysis, Taymans et al. (1998) mapped the CYP11B2 gene to the long arm of chromosome 8, proximal to the microsatellite polymorphic marker D8S1704. Fluorescence in situ hybridization refined the location to 8q24.3.


Gene Function

In in vitro studies using human adrenocortical cell lines, Clyne et al. (1997) demonstrated that CYP11B2 transcription was regulated by angiotensin II (160150) and potassium using the common cis elements cAMP response element (CRE) and steroidogenic factor-1 (SF1; 184757).

Condon et al. (2002) investigated the calcium-dependent mechanism regulating CYP11B2 transcription in a human adrenocortical cell line using a reporter construct containing the 5-prime region of the CYP11B2 gene. They found that CAMK (see CAMK1; 604998) and calmodulin (see CALM1; 114180) inhibitors blocked angiotensin II- and potassium-stimulated CYP11B2 reporter gene expression. CAMK1 augmented reporter expression when cellular calcium was elevated, but CAMK4 (114080) and CAMK2 (see 114078) had little or no effect. A constitutively active CAMK1 mutant stimulated reporter activity. Condon et al. (2002) concluded that CAMK1 is involved in angiotensin II- and potassium-stimulated CYP11B2 transcription.

In studies in rat cardiomyocytes, Tsybouleva et al. (2004) found that aldosterone increased expression of several hypertrophic markers via protein kinase D (PRKCM; 605435) and increased collagens and TGFB1 (190180) via PI3K-delta (PIK3CD; 602839). Inhibition of PRKCM and PIK3CD abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor antagonist spironolactone. In a mouse model of hypertrophic cardiomyopathy (CMH; see 192600), spironolactone reversed interstitial fibrosis, decreased myocyte disarray, and improved diastolic function. Tsybouleva et al. (2004) concluded that aldosterone is a major link between sarcomeric mutations and cardiac phenotype in CMH.


Molecular Genetics

Corticosterone Methyloxidase Type I Deficiency

In 3 Amish infants with corticosterone methyloxidase type I deficiency (CMO I; 203400) characterized by a defect in aldosterone synthesis and severe salt-wasting, Mitsuuchi et al. (1993) identified a homozygous mutation in the CYP11B2 gene (124080.0003). No enzyme was produced and the patients had complete absence of aldosterone.

Corticosterone Methyloxidase Type II Deficiency

In affected individuals from 7 Jewish Iranian families with corticosterone methyloxidase type II deficiency (610600), Pascoe et al. (1992) identified homozygosity for 2 mutations in the CYP11B2 gene: R181W and V386A (124080.0001). Eight asymptomatic individuals were homozygous for R181W alone and 3 asymptomatic individuals were homozygous for V386A alone, suggesting that both substitutions were necessary to cause the disorder. The families had previously been reported by Rosler et al. (1973, 1977), Cohen et al. (1977), and Globerman et al. (1988).

Glucocorticoid-Remediable Aldosteronism

In affected members of a family with glucocorticoid-remediable aldosteronism (GRA; 103900), clinically characterized by hypertension, variable hyperaldosteronism, and increased levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, Lifton et al. (1992) identified a chimeric gene in which the 5-prime regulatory sequences of the CYP11B1 gene were fused to the coding region of the CYP11B2 gene (610613.0002), resulting in ectopic expression of aldosterone synthase in the zona fasciculata. In Australian GRA patients, Miyahara et al. (1992) found that the chimeric gene encoded a fused P-450 protein consisting of the amino-terminal portion (exons 1-4) of CYP11B1 and the carboxyl-terminal part (exons 5-9) of CYP11B2.

Other Associations

Takeda et al. (1999) found increased aldosterone synthase activity and CYP11B2 mRNA expression in mononuclear leukocytes from 9 patients with idiopathic hyperaldosteronism compared to 10 patients with aldosterone-producing adenoma and 10 controls. No chimeric genes or mutations in the coding region of CYP11B2 were found in genomic DNA from these patients. Takeda et al. (1999) suggested that regulatory factors in the CYP11B2 gene may cause overexpression of CYP11B2 mRNA in patients with idiopathic hyperaldosteronism.

Mulatero et al. (2001) described severe hypertension due to paraneoplastic hyperaldosteronism in a 57-year-old man with non-Hodgkin lymphoma (605027). A test for the hybrid CYP11B1-CYP11B2 gene (610613.0002) was negative. Blood pressure returned to normal following chemotherapy, but it again increased as did plasma aldosterone concentrations when the lymphoma relapsed. The patient's lymph node sample showed increased expression of CYP11B2 mRNA. Primary aldosteronism associated with a malignant ovarian tumor has been reported (Todesco et al., 1975).

Tsybouleva et al. (2004) observed that myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4- to 6-fold in patients with hypertrophic cardiomyopathy compared to controls.

Lim et al. (2002) and Nicod et al. (2003) reported an association between 2 polymorphisms in the CYP11B2 gene (-344T-C, 124080.0010 and Int2C, 124080.0011) and an increased aldosterone-to-renin ratio (ARR) among patients with hypertension.

Ganapathipillai et al. (2005) identified 2 main haplotypes defined by SNPs in the CYP11B1 and CYP11B2 genes in independent populations from Europe and South America. The haplotypes consisted of 3 SNPs in the CYP11B2 gene, including -344C-T and Int2C, and 2 SNPs in the CYP11B1 gene. Among both populations, the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Urinary analysis of steroid metabolites showed an association between increased ARR and decreased 11-beta-hydroxylase activity, both associated with the TconvGTA haplotype. The authors concluded that genotypes at the CYP11B locus comprising both genes are in strong linkage disequilibrium and that certain haplotypes predict 11-beta-hydroxylase activity.


ALLELIC VARIANTS 13 Selected Examples):

.0001   CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, ARG181TRP AND VAL386ALA
SNP: rs28931609, rs61757294, gnomAD: rs28931609, rs61757294, ClinVar: RCV000018372, RCV000018373, RCV000272288, RCV000321492, RCV000357616, RCV000949532, RCV001043588, RCV001271159, RCV003463694

In affected individuals from 7 Jewish Iranian families with corticosterone methyloxidase type II deficiency (610600), Pascoe et al. (1992) identified homozygosity for 2 mutations in the CYP11B2 gene: a C-to-T transition in exon 3, resulting in an arg181-to-trp (R181W) substitution, and a T-to-C transition in exon 7, resulting in a val386-to-ala (V386A) substitution. Eight asymptomatic individuals were homozygous for R181W alone and 3 asymptomatic individuals were homozygous for V386A alone, suggesting that both substitutions were necessary to cause the disorder. The families had previously been reported by Rosler et al. (1973, 1977), Cohen et al. (1977), and Globerman et al. (1988). In vitro functional expression studies showed that the R181W mutant enzyme had reduced 18-hydroxylase and undetectable 18-oxidase activities. The V386A substitution caused a small but consistent reduction in the production of 18-hydroxycorticosterone, reflecting some residual 18-hydroxylase activity.

See also Mitsuuchi et al. (1992).


.0002   CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, VAL386ALA AND GLU198ASP
SNP: rs104894072, gnomAD: rs104894072, ClinVar: RCV000018372, RCV000018373, RCV000272288, RCV000321492, RCV000357616, RCV000793582, RCV000949532, RCV001271158, RCV001535987

In 2 French twins with isolated aldosterone synthase deficiency and a biochemical profile typical of CMO I deficiency (203400), Portrat-Doyen et al. (1998) identified homozygosity for 2 pathogenic changes in the CYP11B2 gene: val386-to-ala (V386A) and glu198-to-asp (E198D). Biochemical studies showed decreased aldosterone, decreased 18-OHB, and increased plasma renin, consistent with 18-hydroxylase deficiency. In vitro transfection assays showed that these substitutions individually had modest effects on the encoded enzyme, but when combined they resulted in decreased 11-beta-hydroxylase activity, a large decrease in 18-hydroxylase activity, and no detectable 18-oxidase activity. Portrat-Doyen et al. (1998) concluded that this disparity between the CYP11B2 enzyme with residual 18-hydroxylase activity, a trait more typical of CMO II deficiency (610600), and a biochemical phenotype typical of CMO I deficiency, suggested that phenotype-genotype relationships were not yet fully understood.


.0003   CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, 5-BP DEL
SNP: rs2130336602, ClinVar: RCV000018374

In 3 patients with corticosterone methyloxidase type I deficiency (203400), Mitsuuchi et al. (1993) identified homozygosity for a 5-bp deletion in exon 1 of the CYP11B2 gene, resulting in a frameshift and premature termination of the protein. No enzyme was produced and the patients had complete absence of aldosterone synthesis. Nomoto et al. (1997) stated that the patients with the 5-bp deletion were Amish in origin.


.0004   REMOVED FROM DATABASE


.0005   CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, LEU461PRO
SNP: rs72554627, gnomAD: rs72554627, ClinVar: RCV000018375

In a Turkish patient with CMO I deficiency (203400), Nomoto et al. (1997) identified a homozygous T-to-C transition in exon 8 of the CYP11B2 gene, resulting in a leu461-to-pro (L461P) substitution. The mutation involved a putative heme binding site. In vitro functional expression studies showed that the L461P substitution totally abolished the 18-hydroxylase activity required for conversion of 11-deoxycorticosterone to aldosterone, even though the mutant product was detected in the mitochondrial fraction of the transfected cells.


.0006   CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, GLU255TER
SNP: rs121912977, gnomAD: rs121912977, ClinVar: RCV000018376, RCV001059131, RCV001271156, RCV002250462

In 2 Dutch patients with corticosterone methyloxidase type I deficiency (203400) originally reported by Visser and Cost (1964), Peter et al. (1997) identified a homozygous G-to-T transversion in exon 4 of the CYP11B2 gene, resulting in a glu255-to-ter (E255X) substitution. All 4 parents were heterozygous for the mutation; the family was consanguineous. The mutant enzyme was predicted to lack the 5 terminal exons that contain the heme binding site.

Williams et al. (2004) identified a patient who was compound heterozygous for E255X and a premature termination in codon 272 (124080.0013). The patient displayed a hormonal pattern intermediate between CMO types I and II (610600).


.0007   CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, THR185ILE
SNP: rs121912978, gnomAD: rs121912978, ClinVar: RCV000018377, RCV000808165, RCV001826477, RCV002496398

In a patient with CMO type II deficiency, Peter et al. (1998) demonstrated homozygosity for a C-to-T transition in the CYP11B2 gene, resulting in a thr185-to-ile (T185I) substitution. Both parents were heterozygous carriers for the mutation. The elevated ratio of 18-hydroxycorticosterone to aldosterone in the plasma was considered pathognomonic for CMO deficiency type II. The patient, born of consanguineous Hungarian gypsies, had originally been reported by Hauffa et al. (1991).

Dunlop et al. (2003) reported this mutation, which arises from a 554C-T transition, in an infant with CMO type II deficiency. This patient was compound heterozygous for T185I and a T498A substitution (124080.0012).


.0008   REMOVED FROM DATABASE


.0009   CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CYP11B2, 6-BP DUP, CODON 143
SNP: rs1817623118, ClinVar: RCV000018378

In a patient with CMO type I deficiency (203400), Kayes-Wandover et al. (2001) identified a homozygous 6-bp duplication of 6 nucleotides (CGATTG) in exon 3 of the CYP11B2 gene, resulting in the insertion of 2 amino acids (arginine and leucine) at codon 143. In vitro functional expression studies showed that the mutant enzyme was completely inactive. The patient was unusual in that he presented at age 47 years after developing hyperkalemia in preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. He had increased serum renin with low serum and urinary levels of aldosterone and its metabolites, and normal or slightly elevated levels of 18-hydroxycorticosterone.


.0010   ALDOSTERONE TO RENIN RATIO, INCREASED

CYP11B2, -344C-T
SNP: rs1799998, gnomAD: rs1799998, ClinVar: RCV000018379

Lim et al. (2002) reported an association between a -344C-T polymorphism in the promoter region of the CYP11B2 gene and increased plasma aldosterone-to-renin ratio (ARR) among 326 patients with hypertension. The -344T-C polymorphism disrupts a putative steroidogenic factor-1 (SF1; 184757) binding site. The -344T-C polymorphism is in strong linkage disequilibrium with another polymorphism (Int2C; 124080.0011) in which intron 2 of the CYP11B2 gene is replaced with that from the neighboring CYP11B1 gene (610613). Lim et al. (2002) found significant excesses of -344T and intron 2 conversion alleles in patients with a raised ARR.

Among 141 hypertensive patients, Nicod et al. (2003) found increased frequency of the -344T and Int2C alleles in groups of patients with a high ARR (46% and 43%, respectively) compared to those with a normal ARR (22% and 17%; P less than 0.01 and P less than 0.005, respectively). Odds ratios for raised ARR in subjects with a homozygous -344T and Int2 C haplotype were 6.1 (95% CI, 1.6-22.5; P less than 0.005) when compared with the contrasting haplotype. Linear modeling of individual postural changes in renin and aldosterone showed a maximal achievable aldosterone increase of 110 pmol/liter with no mutated haplotype and 500 pmol/liter with 2 mutated haplotypes. These findings supported the view of a molecular basis regulating aldosterone production.

Mulatero et al. (2006) studied the role of gene polymorphisms of the renin-angiotensin-aldosterone system (RAAS) and of genes involved in sodium handling on blood pressure in acromegaly (102200). Patients with the CYP11B2 -344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4-11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 -344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Mulatero et al. (2006) concluded that there is an association of the -344T/C CYP11B2 gene polymorphism with blood pressure in patients with acromegaly.


.0011   ALDOSTERONE TO RENIN RATIO, INCREASED

CYP11B2, IVS2 CONVERSION
ClinVar: RCV000018380

This variant in the CYP11B2 gene is a polymorphic variant that reflects replacement of the intron 2 from CYP11B2 with that from the neighboring CYP11B1 gene (610613). It is referred to as 'Int2C' for 'intron 2 conversion.'

Lim et al. (2002) and Nicod et al. (2003) reported an increased frequency of the intron 2 conversion allele in hypertensive patients with increased aldosterone-to-renin ratios (see 124080.0010).


.0012   CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, THR498ALA
SNP: rs72554626, ClinVar: RCV000018381, RCV003460485

In an infant with CMO type II deficiency (610600), Dunlop et al. (2003) identified compound heterozygosity for 2 mutations in the CYP11B2 gene: a 1492A-G transition in exon 9, resulting in a thr498-to-ala (T498A) substitution, and T185I (124080.0007). The infant had failure to thrive, persistent hyponatremia, and episodic vomiting and diarrhea. Each unaffected parent was heterozygous for 1 of the mutations. Functional expression studies in COS cells showed steroidogenic patterns typical of CMO type II deficiency, including very low levels of aldosterone synthesis (0.5% or less of wildtype enzyme) consistent with the low aldosterone levels in the patient's plasma. Both mutations localized to the beta-3-sheet in the cytochrome P450 enzyme structure, as does the R181W mutation (124080.0001). Mutations in this region suggest that is important for conferring the unique ability of aldosterone synthase to catalyze efficient oxygenation of the C18 carbon of steroid substrates.


.0013   CORTICOSTERONE METHYLOXIDASE TYPE II DEFICIENCY

CYP11B2, GLU272TER
SNP: rs121912979, ClinVar: RCV000018382

Williams et al. (2004) studied a 4-week-old child of unrelated parents for failure to thrive and salt-wasting with hyperkalemia, high plasma renin, and low-normal aldosterone levels. Urinary metabolite ratios of corticosterone/18-hydroxycorticosterone and 18-hydroxycorticosterone/aldosterone were intermediate between CMO types I (203400) and II (610600). Sequence analysis of the CYP11B2 gene showed that the patient was a compound heterozygote for a previously described E255X mutation (124080.0006) and a glu272-to-ter (Q272X) mutation that arose from a C-to-T transition in exon 5. The patient's unaffected father and mother were heterozygous for the E255X and Q272X mutations, respectively. Thus, the patient had 2 truncated forms of aldosterone synthase predicted to be inactive because they lacked critical active site residues as well as the heme-binding site. This case of CMO was considered of particular interest because despite the apparent lack of aldosterone synthase activity, the patient displayed low-normal aldosterone levels, thus raising the question of its source.


See Also:

Fardella et al. (1996)

REFERENCES

  1. Clyne, C. D., Zhang, Y., Slutsker, L., Mathis, J. M., White, P. C., Rainey, W. E. Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Molec. Endocr. 11: 638-649, 1997. [PubMed: 9139807] [Full Text: https://doi.org/10.1210/mend.11.5.9920]

  2. Cohen, T., Theodor, R., Rosler, A. Selective hypoaldosteronism in Iranian Jews: an autosomal recessive trait. Clin. Genet. 11: 25-30, 1977. [PubMed: 830445] [Full Text: https://doi.org/10.1111/j.1399-0004.1977.tb01273.x]

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Contributors:
John A. Phillips, III - updated : 9/28/2007
Cassandra L. Kniffin - reorganized : 12/13/2006
Cassandra L. Kniffin - updated : 12/6/2006
John A. Phillips, III - updated : 10/20/2006
John A. Phillips, III - updated : 5/18/2006
Patricia A. Hartz - updated : 2/9/2006
Marla J. F. O'Neill - updated : 1/18/2006
John A. Phillips, III - updated : 2/5/2004
John A. Phillips, III - updated : 1/10/2003
John A. Phillips, III - updated : 2/26/2002
John A. Phillips, III - updated : 7/11/2001
Victor A. McKusick - updated : 6/1/2001
John A. Phillips, III - updated : 3/5/2001
John A. Phillips, III - updated : 3/20/2000
John A. Phillips, III - updated : 3/18/1999
Victor A. McKusick - updated : 8/26/1998
John A. Phillips, III - updated : 6/24/1998
John A. Phillips, III - updated : 1/3/1998
Victor A. McKusick - edited : 12/11/1997
Victor A. McKusick - updated : 6/17/1997
John A. Phillips, III - updated : 12/20/1996

Creation Date:
Victor A. McKusick : 6/6/1989

Edit History:
carol : 09/18/2013
terry : 4/29/2009
alopez : 9/28/2007
carol : 12/13/2006
ckniffin : 12/6/2006
alopez : 10/20/2006
wwang : 6/22/2006
alopez : 5/18/2006
mgross : 3/7/2006
terry : 2/9/2006
wwang : 1/18/2006
wwang : 12/13/2005
joanna : 12/6/2005
terry : 5/4/2005
terry : 4/28/2005
carol : 3/17/2004
tkritzer : 2/6/2004
alopez : 2/5/2004
tkritzer : 11/13/2003
tkritzer : 11/10/2003
terry : 11/6/2003
alopez : 10/2/2003
alopez : 1/10/2003
alopez : 6/11/2002
alopez : 6/11/2002
alopez : 2/26/2002
alopez : 2/26/2002
alopez : 7/11/2001
mcapotos : 6/6/2001
mcapotos : 6/5/2001
terry : 6/1/2001
mgross : 3/5/2001
mgross : 3/31/2000
mgross : 3/27/2000
terry : 3/20/2000
mgross : 3/23/1999
mgross : 3/18/1999
mgross : 3/18/1999
carol : 11/25/1998
carol : 9/1/1998
terry : 8/26/1998
dholmes : 6/29/1998
dholmes : 6/24/1998
alopez : 1/26/1998
alopez : 1/26/1998
mark : 12/17/1997
terry : 12/11/1997
terry : 9/8/1997
terry : 9/3/1997
alopez : 6/20/1997
alopez : 6/17/1997
jenny : 5/27/1997
jenny : 5/21/1997
jenny : 5/21/1997
terry : 5/24/1996
terry : 10/12/1994
mimadm : 6/25/1994
warfield : 4/8/1994
carol : 3/22/1993
carol : 3/20/1993
carol : 7/8/1992