Alternative titles; symbols
HGNC Approved Gene Symbol: CYP11A1
Cytogenetic location: 15q24.1 Genomic coordinates (GRCh38): 15:74,337,762-74,367,646 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.1 | Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete | 613743 | 3 |
The cholesterol side-chain cleavage enzyme (P450scc; EC 1.14.15.6), encoded by the CYP11A1 gene, initiates steroidogenesis by converting cholesterol to pregnenolone. P450scc catalyzes 3 consecutive reactions: 20-alpha-hydroxylation, 22-hydroxylation, and scission of the C20,22 carbon bond (summary by Sahakitrungruang et al., 2010).
In steroidogenic tissues such as adrenal cortex, testis, ovary, and placenta, the initial and rate-limiting step in the pathway leading from cholesterol to steroid hormones is the cleavage of the side chain of cholesterol to yield pregnenolone. This reaction, known as cholesterol side-chain cleavage, is catalyzed by a specific form of cytochrome P450 called P450scc or P45011A, which is localized to the inner mitochondrial membrane. Morohashi et al. (1984) and John et al. (1984) cloned the CYP11A1 gene (which is single) from bovine adrenal. There are at least 4 P450 genes expressed in the adrenal; one of the others, that for steroid 21-hydroxylase (613815), is coded by chromosome 6.
Chung et al. (1986) cloned and sequenced full-length human P450scc cDNA. They concluded that the human P450SCC gene is expressed in the placenta in early and mid-gestation because primary cultures of placental tissue showed P450scc mRNA accumulation in response to cyclic AMP.
Morohashi et al. (1987) concluded that the cholesterol desmolase gene is at least 20 kb long and is split into 9 exons by 8 introns.
Nebert et al. (1987) cited evidence that the genes for mitochondrial SCC and steroid 11-beta-hydroxylase (CYP11B1; 610613) are members of the same P450 gene family; therefore, they proposed calling the 2 subfamilies XIA and XIB, respectively. They called the 2 genes XIA1 and XIB1; the gene symbols thus become CYP11A and CYP11B.
Slominski et al. (1996) presented evidence that the CYP11A1, CYP17 (609300), CYP21A2 (613815), and ACTHR (202200) genes are expressed in skin (see 202200). The authors suggested that expression of these genes may play a role in skin physiology and pathology and that cutaneous proopiomelanocortin activity may be autoregulated by a feedback mechanism involving glucocorticoids synthesized locally.
Corticosteroids have specific effects on cardiac structure and function mediated by mineralocorticoid and glucocorticoid receptors (MR and GR (138040), respectively). Aldosterone and corticosterone are synthesized in rat heart. To see whether they might also be synthesized in the human cardiovascular system, Kayes-Wandover and White (2000) examined the expression of genes for steroidogenic enzymes as well as genes for GR, MR, and 11-hydroxysteroid dehydrogenase (HSD11B2; 614232), which maintains the specificity of MR. Human samples were from left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node, as well as whole adult and fetal heart. Using RT-PCR, mRNAs encoding CYP11A, CYP21, CYP11B1, GR, MR, and HSD11B2 were detected in all samples except ventricles, which did not express CYP11B1. CYP11B2 (124080) mRNA was detected in the aorta and fetal heart, but not in any region of the adult heart, and CYP17 was not detected in any cardiac sample. Levels of steroidogenic enzyme gene expression were typically 0.1% those in the adrenal gland. The authors concluded that these findings are consistent with autocrine or paracrine roles for corticosterone and deoxycorticosterone, but not cortisol or aldosterone, in the normal adult human heart.
Using in vitro studies, Guryev et al. (2003) found that CYP11A1 catalyzed the side-chain cleavage of 7-dehydrocholesterol to form 7-dehydropregnenolone. In addition, CYP11A1 catalyzed the metabolism of biologically inert vitamin D3, which is formed from 7-dehydrocholesterol, to form 2 hydroxylated products, 20-hydroxyvitamin D3 and 20,22-dihydroxyvitamin D3.
Chung et al. (1986) localized the CYP11A gene to chromosome 15 by Southern analysis of a panel of mouse-human somatic cell hybrids. Youngblood et al. (1989) demonstrated that the mouse homologs of CYP11A and CYP19 are closely linked on mouse chromosome 9. Thus, it is possible that the CYP11A gene is located in the region 15q21.1, the site of CYP19 in the human. Sparkes et al. (1991) mapped the CYP11A gene to 15q23-q24 by in situ hybridization.
To map the CYP11A gene by linkage analysis, Durocher et al. (1998) used a novel TAAAA polymorphism, found in the promoter region, to genotype the 8 largest CEPH reference families. They performed 2-point linkage analysis between this tetra-allelic polymorphism and the chromosome 15 microsatellite markers of Genethon, as well as the tetranucleotide polymorphism of the CYP19 gene and a MspI RFLP of the CYP1A1 (108330) gene. CYP11A was found to be closely linked to CYP1A1, which was previously mapped to 15q23-q24, but only loosely linked to CYP19, which was previously mapped to 15q22.1. They concluded that the CYP11A gene is located approximately 27.4 cM telomeric to the CYP19 gene.
Congenital Adrenal Insufficiency with 46,XY Sex Reversal
Mutations in the CYP11A1 gene cause congenital adrenal insufficiency with partial or complete 46,XY sex reversal; see 613743.
Association with Polycystic Ovary Syndrome
Because of evidence that an underlying disorder of androgen biosynthesis and/or metabolism is involved in the etiology of polycystic ovary syndrome (PCO; 184700), Gharani et al. (1997) examined the segregation of the genes coding for 2 enzymes in the synthesis and metabolism of androgens, cholesterol side chain cleavage enzyme (CYP11A) and aromatase (CYP19; 107910), with the PCO phenotype in 20 multiply affected families. All analyses excluded CYP19 cosegregation with PCO, demonstrating that this locus is not a major determinant of risk for the syndrome. On the other hand, their results provided evidence for linkage to the CYP11A locus; nonparametric linkage (NPL) score = 3.03, p = 0.003. Parametric analysis using a dominant model suggested genetic heterogeneity, generating a maximum heterogeneity lod score of 2.7. An association study of 97 consecutively identified Europids with PCO and matched controls demonstrated significant allelic association with a pentanucleotide repeat polymorphism in the 5-prime untranslated region of the CYP11A gene in hirsute PCO subjects (p = 0.03). A strong association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected individuals (p = 0.002). The data of Gharani et al. (1997) demonstrated that variation in CYP11A may play an important role in the etiology of the hyperandrogenemia that is a common characteristic of the polycystic ovary syndrome.
Calvo et al. (2001) used heteroduplex analysis to screen the genes encoding STAR (600617), SF1 (184757), DAX1 (NR0B1; 300473), and CYP11A for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. Analysis of CYP11A-coding regions identified a missense mutation in 1 of 29 patients studied. The authors concluded that mutations in STAR, SF1, CYP11A, and DAX1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities found in these women.
Gaasenbeek et al. (2004) reevaluated the relationship between CYP11A promoter variation and PCOS disease status and symptoms and serum testosterone levels. They genotyped a pair of CYP11A promoter microsatellites, including the pentanucleotide implicated in trait susceptibility (Gharani et al., 1997), in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1,589 women from a population-based birth cohort from Finland characterized for polycystic ovary symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study, these findings were not substantiated in the other analyses, and no discernible relationship was seen between variation at these loci and serum testosterone levels. The authors concluded that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes had been substantially overestimated in previous studies.
In a patient with adrenal insufficiency and 46,XY sex reversal (613743), Tajima et al. (2001) identified heterozygosity for an in-frame 6-bp insertion in exon 4 of the CYP11A gene. The mutation, which introduced gly and asp codons between asp271 and val272, was inserted into a catalytically active fusion protein of the CYP11A system, and completely inactivated enzymatic activity. The mutation was found in multiple cell types, but neither parent carried the mutation, suggesting it arose de novo during meiosis, before fertilization. Cotransfection of wildtype and mutant vectors showed that the mutation did not exert a dominant-negative effect. The patient was encountered in a study of patients with clinical features of congenital lipoid adrenal hyperplasia (201710). No mutations were present in the STAR (600617) and SF1 (184757) genes.
In a female patient with congenital adrenal insufficiency (613743) born to healthy parents, Katsumata et al. (2002) reported compound heterozygous mutations in the CYP11A gene. One mutation, a maternally inherited arg353-to-trp (R353W) mutation, resulted in markedly reduced P450scc activity by the single amino acid substitution, indicating that arg353 is a crucial amino acid residue for P450scc activity. The other mutation, a de novo ala189-to-val (A189V) mutation in the paternal allele, did not affect the P450scc activity by the single amino acid substitution; the mutation resulted in a nucleotide sequence with considerable homology to the consensus splice donor site sequence, and created a novel alternative splice donor site. It resulted in a deletion of 61 nucleotides in the open reading frame and thus partially inactivated CYP11A. These experimental data were consistent with the clinical findings indicating that the patient had partially preserved ability to synthesize adrenal steroid hormones. The 46,XX patient was born with dark skin, but adrenal insufficiency was not clinically manifest until the age of 7 months.
For discussion of the ala189-to-val (A189V) mutation in the CYP11A1 gene that was found in compound heterozygous state in a female patient with congenital adrenal insufficiency (613743) by Katsumata et al. (2002), see 118485.0002.
Hiort et al. (2005) reported a 46,XY patient with a homozygous defect of CYP11A1. This child was born prematurely with sex reversal and severe adrenal insufficiency (613743). Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single-nucleotide deletion of adenine at position 835 in exon 5, leading to a premature termination at codon 288. This mutation was predicted to delete highly conserved regions of the P450scc enzyme and thus to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Hiort et al. (2005) stated that this was the first report of an inherited disruptive mutation in the CYP11A1 gene.
Kim et al. (2008) described a patient with 46,XY sex reversal and primary adrenal failure who was compound heterozygous for the 835delA mutation and a splice site mutation (IVS3+(2-3)insT; 118485.0006). External genitalia were those of a normal female; no gonads, internal reproductive structures, or adrenals were identified by MRI or ultrasound, and a genitogram revealed a blind vaginal pouch. Functional studies in COS-1 cells demonstrated no activity of 835delA-mutated P450scc. The IVS3+(2-3)insT mutation introduces an additional thymidine after the second base of the third intron that was predicted to disrupt the splice donor site. PCR amplification of RNA demonstrated that sequences corresponding to intron 3 had been retained, resulting in a nonfunctional protein.
Sahakitrungruang et al. (2010) identified the 835delA mutation in 2 sibs with adrenal insufficiency. The 46,XY sib had micropenis, severe hypospadias, bifid scrotum, and cryptorchidism; the other sib was 46,XX with normal female genitalia. The sibs carried the 835delA mutation in compound heterozygosity with a missense mutation.
In a 46,XY phenotypic female, born at term to healthy consanguineous parents, who presented relatively late at the age of 1 year 9 months with life-threatening adrenal insufficiency and complete sex reversal (613743), al Kandari et al. (2006) identified homozygosity for a C-to-T transition in exon 6 of the CYP11A1 gene, resulting in an ala359-to-val (A359V) substitution. The patient was also found to have complete agenesis of the corpus callosum. Functional analysis of the mutant enzyme revealed markedly reduced enzyme activity, with about 11% residual activity. The parents were heterozygous for the mutation.
For discussion of the splice site mutation (IVS3+(2-3)insT) in the CYP11A1 gene that was found in compound heterozygous state in a patient with 46,XY sex reversal and primary adrenal failure (613743) by Kim et al. (2008), see 118485.0004.
Kim et al. (2008) described a patient with 46,XY sex reversal and adrenal insufficiency (613743) who was compound heterozygous for missense mutations in the CYP11A1 gene. The maternal allele carried a 422T-G transversion resulting in a leu141-to-trp substitution (L141W), and the paternal allele carried a 1244T-A transversion resulting in a val415-to-glu substitution (V415E; 118485.0008). External genitalia were those of a normal female. Pelvic ultrasonography revealed bilateral intraabdominal gonads and no uterus. The L141W mutant protein retained 38.5% activity of wildtype in functional assays. The V415E mutation lacked any detectable activity to convert cholesterol to pregnenolone in functional assays.
For discussion of the val415-to-glu (V415E) mutation in the CYP11A1 gene that was found in compound heterozygous state in a patient with 46,XY sex reversal and adrenal insufficiency (613743) by Kim et al. (2008), see 118485.0007.
In a patient with late-onset adrenal insufficiency and hypospadias (613743), Rubtsov et al. (2009) found homozygosity for a 666T-C transition in exon 3 of the CYP11A1 gene that resulted in substitution of proline for leucine at codon 222 (L222P). The patient presented with midshaft hypospadias and cryptorchidism at birth and signs of adrenal failure at 9 years of age. Functional expression analyses demonstrated that the mutant protein had significantly reduced but detectable activity estimated to be 6.9% of normal.
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Calvo, R. M., Asuncion, M., Telleria, D., Sancho, J., San Millan, J. L., Escobar-Morreale, H. F. Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women. J. Clin. Endocr. Metab. 86: 1746-1749, 2001. [PubMed: 11297612] [Full Text: https://doi.org/10.1210/jcem.86.4.7424]
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Guryev, O., Carvalho, R. A., Usanov, S., Gilep, A., Estabrook, R. W. A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1). Proc. Nat. Acad. Sci. 100: 14754-14759, 2003. [PubMed: 14657394] [Full Text: https://doi.org/10.1073/pnas.2336107100]
Hiort, O., Holterhus, P.-M., Werner, R., Marschke, C., Hoppe, U., Partsch, C.-J., Riepe, F. G., Achermann, J. C., Struve, D. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure. J. Clin. Endocr. Metab. 90: 538-541, 2005. [PubMed: 15507506] [Full Text: https://doi.org/10.1210/jc.2004-1059]
John, M. E., John, M. C., Ashley, P., MacDonald, R. J., Simpson, E. R., Waterman, M. R. Identification and characterization of cDNA clones specific for cholesterol side-chain cleavage cytochrome P-450. Proc. Nat. Acad. Sci. 81: 5628-5632, 1984. [PubMed: 6592578] [Full Text: https://doi.org/10.1073/pnas.81.18.5628]
Katsumata, N., Ohtake, M., Hojo, T., Ogawa, E., Hara, T., Sato, N., Tanaka, T. Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J. Clin. Endocr. Metab. 87: 3808-3813, 2002. [PubMed: 12161514] [Full Text: https://doi.org/10.1210/jcem.87.8.8763]
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Kim, C. J., Lin, L., Huang, N., Quigley, C. A., AvRuskin, T. W., Achermann, J. C., Miller, W. L. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J. Clin. Endocr. Metab. 93: 696-702, 2008. [PubMed: 18182448] [Full Text: https://doi.org/10.1210/jc.2007-2330]
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Rubtsov, P., Karmanov, M., Sverdlova, P., Spirin, P., Tiulpakov, A. A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient. J. Clin. Endocr. Metab. 94: 936-939, 2009. [PubMed: 19116240] [Full Text: https://doi.org/10.1210/jc.2008-1118]
Sahakitrungruang, T., Tee, M. K., Blackett, P. R., Miller, W. L. Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. J. Clin. Endocr. Metab. 96: 792-798, 2010. [PubMed: 21159840] [Full Text: https://doi.org/10.1210/jc.2010-1828]
Slominski, A., Ermak, G., Mihm, M. ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. J. Clin. Endocr. Metab. 81: 2746-2749, 1996. [PubMed: 8675607] [Full Text: https://doi.org/10.1210/jcem.81.7.8675607]
Sparkes, R. S., Klisak, I., Miller, W. L. Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24; adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25. DNA Cell Biol. 10: 359-365, 1991. [PubMed: 1863359] [Full Text: https://doi.org/10.1089/dna.1991.10.359]
Tajima, T., Fujieda, K., Kouda, N., Nakae, J., Miller, W. L. Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J. Clin. Endocr. Metab. 86: 3820-3825, 2001. [PubMed: 11502818] [Full Text: https://doi.org/10.1210/jcem.86.8.7748]
Youngblood, G. L., Nesbitt, M. N., Payne, A. H. The structural genes encoding P450SCC and P450AROM are closely linked on mouse chromosome 9. Endocrinology 125: 2784-2786, 1989. [PubMed: 2792009] [Full Text: https://doi.org/10.1210/endo-125-5-2784]