Alternative titles; symbols
HGNC Approved Gene Symbol: CYP11B1
SNOMEDCT: 124214007, 703232003; ICD10CM: E26.02; ICD9CM: 255.11;
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:142,872,357-142,879,825 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency | 202010 | Autosomal recessive | 3 |
| Aldosteronism, glucocorticoid-remediable | 103900 | Autosomal dominant | 3 |
The CYP11B1 gene encodes a steroid 11-beta-hydroxylase (EC 1.14.15.4) that functions primarily in mitochondria in the zona fasciculata of the adrenal cortex to convert 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone.
CYP11B1 shows close homology to the CYP11B2 gene (124080), which encodes aldosterone synthase and is normally expressed only in the zona glomerulosa. Both genes map to chromosome 8q21.
Nebert et al. (1987) cited evidence that the steroid 11-beta-hydroxylase gene is in the same P450 gene family as the gene for SCC, or P450 side-chain cleavage enzyme (CYP11A1; 118485). They proposed that the subfamilies be referred to as XIA for SCC and XIB for 11-beta-hydroxylase.
Chua et al. (1987) isolated human adrenal cDNA clones corresponding to the CYP11B1 gene.
Mornet and White (1989) cloned the CYP11B1 gene. The 502-amino acid protein includes a 24-residue mitochondrial signal sequence.
Mornet and White (1989) determined that the CYP11B1 gene contains 9 exons and spans 6.5 kb. The 8 introns are identical in location to the introns of CYP11A1 (118485), another mitochondrial P450 enzyme gene, confirming that both belong to the P450 superfamily.
White et al. (1987) stated that the CYP11B1 gene is present in the human genome in a single copy on the long arm of chromosome 8. The assignment was performed by in situ hybridization and by Southern blot analysis of DNA from human-mouse somatic cell hybrids.
By somatic cell hybridization and in situ hybridization, Chua et al. (1987) localized the P450C11 gene to chromosome 8q21.
Levine et al. (1980) presented evidence that the 11-beta-hydroxylase systems in the adrenal zona fasciculata and zona glomerulosa are separate. They also found evidence suggesting that the 11-beta- and 18-hydroxylating activities of the fasciculata are functionally related and may involve the same enzyme protein and catalytic site. Both 11-beta- and 18-hydroxylase appeared to be deficient in the fasciculata but normal in the glomerulosa.
Using RT-PCR, Kayes-Wandover and White (2000) detected CYP11B1 mRNA in human cardiac tissue samples from left and right atria, aorta, apex, intraventricular septum, and atrioventricular node, as well as whole adult and fetal heart. Ventricles did not express CYP11B1. Levels of steroidogenic enzyme gene expression were typically 0.1% those in the adrenal gland. The authors concluded that cortisol does not show autocrine or paracrine activity in normal adult human heart.
Congenital Adrenal Hyperplasia due to Steroid 11-Beta-Hydroxylase Deficiency
In affected individuals of Moroccan Jewish ancestry with congenital adrenal hyperplasia due to steroid 11-beta-hydroxylase deficiency (202010), White et al. (1991) identified a homozygous mutation in the CYP11B1 gene (R448H; 610613.0001). The mutation was found in 11 of 12 mutant alleles from 6 families. In a screening for the R448H mutation in 236 healthy Moroccan Jews, Paperna et al. (2005) identified only 2 carriers of the mutation. suggesting that the high incidence of CAH due to steroid 11-beta-hydroxylase deficiency in the Moroccan Jewish population is only partially explained by the presence of R448H as a founder mutation.
In patients with 11-beta-hydroxylase deficiency leading to hypertension and congenital adrenal hyperplasia, Pascoe et al. (1992) identified mutations in the CYP11B1 gene (see, e.g., 610613.0003; 610613.0004).
Curnow et al. (1993) identified 8 mutations in the CYP11B1 gene causing hypertensive CAH. They noted that 7 of a total of 10 known mutations are clustered in exons 6-8. Geley et al. (1996) identified 7 mutations in the CYP11B1 gene in 9 patients with CAH due to 11-beta-hydroxylase deficiency. A Caucasian patient was homozygous for the R448H mutation previously found in Jews of Moroccan origin. All of the mutations resulted in a complete loss of steroid 11-beta-hydroxylating activity when expressed in cultured cells.
In a screening of individuals with 11-beta-hydroxylase deficiency, Skinner et al. (1996) identified a G-to-T transversion in exon 9 of the CYP11B1 gene, resulting in a cys494-to-phe (C494F) substitution. They identified 1 Indian and 2 Turkish sib patients who were homozygous for the mutation. In further studies, Loidi et al. (1999) found homozygosity for the C494F substitution in 10 chromosomes of patients suspected of having 11-beta-hydroxylase deficiency and 40 chromosomes of normal Spanish people, consistent with a polymorphism. The substitution is located 10 amino acids from the C terminus of the protein and likely does not affect enzymatic activity.
Glucocorticoid-Remediable Aldosteronism
In affected members of a family with autosomal dominant 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
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.
Keavney et al. (2005) measured levels of plasma 11-deoxycortisol (S) and cortisol (F) in 460 Caucasian individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 Caucasian individuals from 105 families. All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P less than 0.00001), and there was strong linkage disequilibrium across the CYP11B1/B2 locus. There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for a CYP11B1 exon 1 polymorphism (P = 0.00002). Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population.
To investigate the role of CYP11B1/B2 polymorphisms in adrenal steroid metabolism, Imrie et al. (2006) studied genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism in 573 members of 105 British families ascertained through a hypertensive proband. The heritability of urinary tetrahydroaldosterone (THAldo) excretion was 52% (P less than 10(-6)). There was significant association between THAldo and genotype at several CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Imrie et al. (2006) concluded that aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1.
A polymorphism in the gene for steroid 11-beta-hydroxylase that cosegregates with the adrenal capacity to synthesize 18-OH-DOC and with blood pressure is apparently responsible for the resistance of a particular strain of Dahl rat to hypertension when fed a high NaCl diet. The gene is located on rat chromosome 7. The rat allele for resistance encodes 5 amino acid substitutions in the 11-beta-hydroxylase protein (Cicila et al., 1993).
Mullins et al. (2009) found that Cyp11b1 -/- mice were viable and that male, but not female, Cyp11b1 -/- mice were fertile. Both sexes exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, hypokalemia, and glucose intolerance. They also showed increased urinary testosterone and progesterone. The ovaries of Cyp11b1 -/- mice lacked corpora lutea and showed central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that increased progesterone levels contributed to their infertility.
In affected individuals of Moroccan Jewish ancestry with congenital adrenal hyperplasia due to steroid 11-beta-hydroxylase deficiency (202010), White et al. (1991) identified a G-to-A transition in exon 8 of the CYP11B1 gene, resulting in an arg448-to-his (R448H) substitution in a highly conserved residue. The mutation was found in 11 of 12 mutant alleles from 6 families. Most of the patients had previously been reported by Rosler et al. (1982).
In a screening for the R448H mutation in 236 healthy Moroccan Jews, Paperna et al. (2005) identified only 2 carriers of the mutation.
In affected members of a family with glucocorticoid-remediable aldosteronism (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 (124080), which encodes aldosterone synthase, resulting in ectopic expression of aldosterone synthase in the zona fasciculata. The 2 genes were closely linked in a head-to-tail orientation with the CYP11B2 gene 5-prime to the CYP11B1 gene. The chimeric gene is of the anti-Lepore type, as in hemoglobin Miyada (141900.0179). Polymorphic markers of the CYP11B1 and CYP11B2 genes showed complete linkage (maximum lod score = 3.63), indicating that these are contiguous genes. Lifton et al. (1992) referred to the change as a neomorphic mutation. They suggested that aberrations of this type leading to hypertension inherited as an autosomal dominant trait may be more frequent than previously realized.
See 610613.0014 and Ezquieta and Luzuriaga (2004) for a description of a deletion hybrid that appears to be the reciprocal recombination product to this duplication hybrid.
In a patient with steroid 11-beta-hydroxylase deficiency leading to hypertension and congenital adrenal hyperplasia (202010), Pascoe et al. (1992) identified a mutation in the CYP11B1 gene, resulting in a thr318-to-met (T318M) substitution. In vitro functional expression studies in COS-1 cells showed that the substitution led to complete loss of 11-beta-hydroxylase activity.
In a patient with steroid 11-beta-hydroxylase deficiency leading to hypertension and congenital adrenal hyperplasia (202010), Pascoe et al. (1992) identified a mutation in the CYP11B1 gene, resulting in an arg374-to-gln (R374Q) substitution. In vitro functional expression studies in COS-1 cells showed that the substitution led to complete loss of 11-beta-hydroxylase activity.
In an 8-year-old boy of Turkish origin, born of consanguineous parents, with congenital adrenal hyperplasia due to steroid 11-beta-hydroxylase deficiency (202010), Helmberg et al. (1992) identified a homozygous 2-bp insertion in codon 394 in exon 7 of the CYP11B1 gene, resulting in a frameshift and a premature stop in codon 469, resulting in complete destruction of the enzyme's heme-binding domain. The patient had marked hypertension, precocious pseudopuberty, and completely virilized intersexual genitalia with a 46,XX karyotype. Ultrasound examination disclosed adrenal hyperplasia and the existence of a uterus and vagina ending in the proximal urethra. Four sibs of the patient died shortly after birth or in early childhood.
In a 27-year-old Japanese man, born of consanguineous parents, with congenital adrenal hyperplasia due to steroid 11-beta-hydroxylase deficiency (202010), Naiki et al. (1993) identified a G-to-A transition in exon 2 of the CYP11B1 gene, resulting in a trp116-to-ter (W116X) substitution. The patient had a 46,XY karyotype and height of 145.6 cm. The diagnosis had been made at the age of 1 year when he was admitted to the hospital because of excessive growth, without complaints of poor feeding, nausea, or vomiting. He was treated with cortisol and later with dexamethasone.
In a female patient with partial steroid 11-beta-hydroxylase deficiency (202010), Joehrer et al. (1997) found compound heterozygosity for 2 mutations in the CYP11B1 gene: asn133-to-his (N133H) and thr319-to-met (T319M; 610613.0008). The patient was diagnosed at 8 years of age with a bone age of 11 years. Her height was greater than the 95th percentile. This mutation was associated with approximately 15 to 40% enzyme activity.
See 610613.0007 and Joehrer et al. (1997).
In a patient with partial steroid 11-beta-hydroxylase deficiency (202010), Joehrer et al. (1997) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: a pro42-to-ser (P42S) substitution and a nonsense mutation (Y423X; 610613.0015). The patient, diagnosed at 5 years of age with an advanced bone age of 12 years, was in the 75th percentile for height and had acne and precocious puberty. The proline at codon 42 is conserved in all CYP11B isozymes and in rather distantly related enzymes such as P450cam (EC 1.14.15.1). A mutation at the corresponding position in CYP21 (P30L; 201910.0004) causes mild 21-hydroxylase deficiency. The protein carrying the P42S mutation retained partial enzyme activity.
In a patient with CAH due to steroid 11-beta-hydroxylase deficiency (202010), Chabre et al. (2000) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: a 954G-C transversion in exon 5, resulting in a conservative thr318-to-thr (T318T) substitution, and an A-to-G transition in intron 8 (IVS8+4A-G; 610613.0011). The genetically female patient was raised as a male because of severe pseudohermaphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension with pronounced hypertrophic cardiomyopathy. At 42 years of age the occurrence of central retinal vein occlusion with permanent loss of left eye vision led to the decision to perform bilateral laparoscopic adrenalectomy. Surgery was followed by normalization of blood pressure and good compliance with glucocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low CYP11B1 activity. Western blot analysis showed weak expression of a shorter CYP11B immunoreactive band of 43 kD, consistent with truncation of exon 8. Exon 8 of the CYP11B1 gene encodes the binding region of the heme prosthetic group necessary for the enzymatic activity; in vitro studies demonstrated that the truncated P450c11 protein was not functional.
For discussion of the splice site mutation (IVS8+4A-G) in the CYP11B1 gene that was found in compound heterozygous state in a patient with CAH due to steroid 11-beta-hydroxylase deficiency (202010) by Chabre et al. (2000), see 610613.0010.
Hampf et al. (2001) reported a case of steroid 11-beta-hydroxylase deficiency (202010) caused by an unequal crossover of the genes encoding aldosterone synthase (CYP11B2; 124080) and 11-beta-hydroxylase (CYP11B1). CYP11B1 and CYP11B2 are located on chromosome 8q24 approximately 45 kb apart from each other. The investigated genetic recombination deleted the normal alleles of the 2 genes and created a chimeric fusion gene, which consists of the promoter and exons 1 through 4 of the CYP11B2 gene plus intron 4 through exon 9 of the CYP11B1 gene. This recombination event subordinated any remaining CYP11B1 activity of the chimeric enzyme to the control mechanisms of CYP11B2, the expression of which is mainly regulated by angiotensin II (see 106150) and potassium. Normally the CYP11B1 activity is controlled by ACTH. Furthermore, by applying a minigene expression method, Hampf et al. (2001) demonstrated a point mutation in intron 3 (IVS3+16G-T; 610613.0013) of the patient's second CYP11B1 allele that radically diminished proper splicing of the pre-mRNA by giving rise to a new, highly preferred donor splice site.
On the paternal allele of a patient with steroid 11-beta-hydroxylase deficiency (202010), Hampf et al. (2001) identified a G-to-T transversion at position 16 of intron 3 of the CYP11B1 gene. This mutation led to a 14-basepair insertion between exons 3 and 4, causing a frameshift and premature translation stop in exon 4 (codon 226 of the mutated RNA).
In a Caucasian Spanish boy with CAH due to steroid 11-beta-hydroxylase deficiency (202010), Ezquieta and Luzuriaga (2004) identified homozygosity for a gene deletion hybrid with a breakpoint at exon 4. Residues at exon 3 and at the beginning of exon 4, including position 202, were characteristic of CYP11B2, whereas the residue at position 248 of exon 4 and others in exons 5-9 were characteristic of CYP11B1. The patient presented with a salt-wasting episode during the neonatal period. At 22 months of age, the patient exhibited acceleration of growth, precocious pubarche, and macrogenitalia, and hormonal levels were consistent with a diagnosis of 11-beta-hydroxylase deficiency. By age 8.8 years, episodes of hypertension were documented, and antihypertensive treatment was required after age 17. Ezquieta and Luzuriaga (2004) stated that a homozygous chimeric genotype in a nonconsanguineous family is a rare finding, and suggested that this deletion hybrid is the reciprocal product from the recombination event resulting in a duplication dominant allele (610613.0002) that causes glucocorticoid-remediable aldosteronism (103900).
In a patient with partial steroid 11-beta-hydroxylase deficiency (202010), Joehrer et al. (1997) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: tyr423-to-ter (Y423X) and P42S (610613.0009).
In a 1.8-year-old boy with CAH due to steroid 11-beta-hydroxylase deficiency (202010), Krone et al. (2006) identified compound heterozygosity for 2 mutations in the CYP11B1 gene: a 281C-T transition in exon 2 that resulted in a pro94-to-leu (P94L) substitution, and a 1103C-A transversion in exon 6 that resulted in an ala368-to-asp (A368D) substitution (610613.0017). In vitro expression studies in COS-7 cells revealed an almost complete absence of CYP11B1 activity for the P94L mutant to 0.05% for the conversion of 11-deoxycortisol to cortisol. The A368D mutant also resulted in severe reduction of CYP11B1 enzyme activity to 1.17%. According to structural analysis, only a minor effect of the P94L mutant on 11-hydroxylase activity was predicted, which contrasted with the observed major effect of this mutation both in vitro and in vivo. Krone et al. (2006) noted that the combination of in vitro enzyme function and molecular modeling may provide valuable insights in cytochrome P450 structural-functional relationships.
For discussion of the ala368-to-asp (A368D) mutation in the CYP11B1 gene that was found in compound heterozygous state in a boy with CAH due to steroid 11-beta-hydroxylase deficiency (202010) by Krone et al. (2006), see 610613.0016.
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