Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 603711

CYTOCHROME P450, FAMILY 7, SUBFAMILY B, POLYPEPTIDE 1; CYP7B1

Alternative titles; symbols

OXYSTEROL 7-ALPHA-HYDROXYLASE 1

HGNC Approved Gene Symbol: CYP7B1

SNOMEDCT: 763373005;

Cytogenetic location: 8q12.3 Genomic coordinates (GRCh38) : 8:64,586,575-64,798,737 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

The synthesis of primary bile acids from cholesterol occurs via 2 pathways: the classic neutral pathway involving cholesterol 7-alpha-hydroxylase (CYP7A1; 118455), and the acidic pathway involving a distinct microsomal oxysterol 7-alpha-hydroxylase (CYP7B1).

Cloning and Expression

Setchell et al. (1998) cloned and characterized a cDNA for CYP7B1.

Gene Structure

Setchell et al. (1998) determined that the CYP7B1 gene contains 6 exons. The positions of the 5 introns are identical to those of the CYP7A1 gene.

Mapping

By radiation hybrid analysis, Setchell et al. (1998) mapped the CYP7A1 gene to chromosome 8q21.13 and the CYP7B1 gene to 8q21.3. The close linkage of the genes and their shared exon-intron structures suggested that they arose via an ancient duplication event.

Gene Function

Using RT-PCR and mRNA in situ hybridization, Martin et al. (2004) determined and localized the expression of CYP7B mRNA in human benign prostatic hyperplasia. High levels of CYP7B mRNA were localized in the epithelial cells together with estrogen receptor beta (ER-beta; 601663). To investigate the functional relevance of CYP7B expression to sex steroid action in prostate, they used transient transfections and ligand binding assay to determine the ability of 7-alpha-hydroxy-DHEA (7HD) to bind and activate the sex steroid receptors androgen receptor (AR; 313700), ER-alpha (133430), and ER-beta. 7HD specifically activated ER-beta-mediated transcription, mimicking the effects of 17-beta-estradiol, but had no impact on ER-alpha or AR. Given that DHEA and its sulfate circulate at micromolar concentrations, Martin et al. (2004) concluded there is a clear possibility that CYP7B generates sufficient 7HD to activate ER-beta over and above that achieved with very low concentrations of intraprostatic 17-beta-estradiol. They also concluded that their study suggested that CYP7B catalyzes oxysterol 7-alpha-hydroxylation within the human prostate epithelium.

Choi et al. (2019) showed that the CH25H (604551)-CYP7B1-ROR-alpha (600825) axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. They found that mouse osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1), and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, ROR-alpha was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. Choi et al. (2019) concluded that their results indicated that osteoarthritis is a disease associated with metabolic disorders and suggested that targeting the CH25H-CYP7B1-ROR-alpha axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

Molecular Genetics

Congenital Bile Acid Synthesis Defect 3

In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), Setchell et al. (1998) identified a homozygous mutation in the CYP7B1 gene (R388X; 603711.0001).

In a Taiwanese infant with CBAS3, Ueki et al. (2008) identified a homozygous nonsense mutation in the CYP7B1 gene (R112X; 603711.0011). The mutation, which was found by exome sequencing of the CYP7B1 and CYP7A1 genes, was present in heterozygous state in the parents. The mutation was not found in 102 controls.

Spastic Paraplegia 5A, Autosomal Recessive

In affected individuals of 5 families with autosomal recessive spastic paraplegia (SPG5A; 270800), Tsaousidou et al. (2008) identified homozygous mutations in the CYP7B1 gene (603711.0002-603711.0005). An additional patient with sporadic SPG5A was found to be homozygous for the R388X mutation. All patients had a pure form of motor neuron degeneration with progressive spastic paraplegia and variable bladder and sensory impairment. The findings indicated a primary metabolic route for the modification of neurosteroids in the brain and a indicated pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease.

Biancheri et al. (2009) identified a mutation in the CYP7B1 gene (G57R; 603711.0003) in 1 (8%) of 12 families with autosomal recessive SPG, suggesting that it is a relatively uncommon cause of the disorder.

Goizet et al. (2009) identified 8 different mutations, including 6 novel mutations, in the CYP7B1 gene (see, e.g., 603711.0007 and 603711.0008) in 6 (7.3%) of 82 unrelated kindreds with autosomal recessive SPG and in 3 (3.3%) of 90 individuals with sporadic SPG. Most individuals had pure forms of SPG5A, although some patients had additional features.

Animal Model

Using immunoblotting, Li-Hawkins et al. (2000) detected higher levels of Cyp7b1 protein in the liver and kidney of male mice compared with female mice.

Li-Hawkins et al. (2000) produced mice carrying a targeted disruption in Cyp7b1. The knockout mice had elevated levels of 2 different oxysterols, 25-hydroxycholesterol and 27-hydroxycholesterol, in serum and tissue. De novo cholesterol synthesis was decreased by approximately 40% in the kidneys of male knockout mice. Li-Hawkins et al. (2000) concluded that the major physiologic role of Cyp7b1 is to inactivate oxysterols and that loss of this enzyme in the liver of mice is compensated for by an increase in the synthesis of bile acids by other pathways (see CYP39A1, 605994).

Biddinger et al. (2008) generated liver-specific Insr (147670)-knockout mice and observed a marked predisposition to cholesterol gallstone formation that was due in part to decreased expression of the bile acid synthetic enzymes, particularly Cyp7b1, which produced partial resistance to the farnesoid X receptor (NR1H4; 603826), leading to a lithogenic bile salt profile.

ALLELIC VARIANTS 11 Selected Examples):

.0001 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 3

SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE, INCLUDED

CYP7B1, ARG388TER
SNP: rs72554620, gnomAD: rs72554620, ClinVar: RCV000006473, RCV000006474, RCV000800899

Congenital Bile Acid Synthesis Defect 3

In a 10-week-old boy with a metabolic defect in bile acid synthesis involving a deficiency in 7-alpha-hydroxylation (CBAS3; 613812), Setchell et al. (1998) identified a homozygous C-to-T transition in the CYP7B1 gene, resulting in an arg388-to-ter (R388X) substitution.

Spastic Paraplegia 5A

In a patient with sporadic spastic paraplegia-5A (SPG5A; 270800), Tsaousidou et al. (2008) identified a homozygous 1162C-T transition in the CYP7B1 gene, resulting in an R388X substitution. The patient had symptoms of pure motor neuron degeneration without other features. Tsaousidou et al. (2008) postulated that the patient reported by Setchell et al. (1998) may have had loss of both alpha-hydroxylating enzymes, CYP7B1 and CYP7A1 (118455), to result in such a severe phenotype.

.0002 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, SER363PHE
SNP: rs121908610, gnomAD: rs121908610, ClinVar: RCV000006475, RCV001847590, RCV003750776

In affected members of a large consanguineous English family with spastic paraplegia-5A (SPG5A; 270800) reported by Wilkinson et al. (2003), Tsaousidou et al. (2008) identified a homozygous 1088C-T transition in exon 5 of the CYP7B1 gene, resulting in a ser363-to-phe (S363F) substitution. The substitution was predicted to abolish a phosphorylation site in the mature protein.

.0003 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, GLY57ARG
SNP: rs121908614, gnomAD: rs121908614, ClinVar: RCV000006476

In affected members of a Tunisian family with spastic paraplegia-5A (SPG5A; 270800) reported by Hentati et al. (1994), Tsaousidou et al. (2008) identified a homozygous 169G-A transition in exon 2 of the CYP7B1 gene, resulting in a gly57-to-arg (G57R) substitution.

In 2 Italian brothers with SPG5A, Biancheri et al. (2009) identified homozygosity for the G57R mutation. The mutation was not identified in 200 control chromosomes. The 20-year-old proband had a history of delayed walking and difficulty walking and running in childhood. Physical examination at age 20 showed spastic paraparesis, but he could walk unaided. Brain MRI showed white matter changes in the supra and infratentorial compartment and spinal cord thinning, without signal abnormalities. His affected brother lost the ability to walk independently at age 19, and brain MRI showed similar, but milder, white matter changes. Biancheri et al. (2009) noted that the CYP7B1 gene is involved in cholesterol and neurosteroid metabolism in the brain, which could be related to the white matter changes.

.0004 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, ARG417HIS
SNP: rs121908611, gnomAD: rs121908611, ClinVar: RCV000006477, RCV000206595, RCV000329074, RCV001847591, RCV003894794

In affected members of 2 consanguineous Tunisian families with spastic paraplegia-5A (SPG5A; 270800) reported by Hentati et al. (1994), Tsaousidou et al. (2008) identified a homozygous 1250G-A transition in exon 6 of the CYP7B1 gene, resulting in an arg417-to-his (R417H) substitution.

Goizet et al. (2009) identified a homozygous R417H mutation in affected members of a family with SPG5A and in a patient with sporadic disease. Another family was compound heterozygous for R417H and F470I (603711.0008). Patients who were homozygous for the mutation presented a pure SPG, with mild to moderate lower limb involvement and decreased vibratory sensation. Some patients showed mild upper limb weakness.

.0005 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, PHE216SER
SNP: rs121908612, ClinVar: RCV000006478

In affected members of a family with spastic paraplegia-5A (SPG5A; 270800), Tsaousidou et al. (2008) identified a homozygous 647T-C transition in exon 3 of the CYP7B1 gene, resulting in a phe216-to-ser (F216S) substitution. The substitution was predicted to create a novel phosphorylation site in the mature protein.

.0006 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, TYR275TER
SNP: rs121908613, gnomAD: rs121908613, ClinVar: RCV000006479, RCV000260437, RCV000515995, RCV000553161

In a 41-year-old woman with spastic paraplegia-5A (SPG5A; 270800), Schule et al. (2009) identified a homozygous 825T-A transversion in the CYP7B1 gene, resulting in a tyr275-to-ter (Y275X) substitution. The patient developed SPG at age 18 and also had optic atrophy. There was no family history of SPG. At age 41, she had spastic paraparesis, used a walking frame, and had distal sensory deficits clinically.

.0007 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, PHE470ILE
SNP: rs267606758, ClinVar: RCV000006480

In 4 affected members of a family with complicated spastic paraplegia-5A (SPG5A; 270800), Goizet et al. (2009) identified compound heterozygosity for 2 mutations in the CYP7B1 gene: a 1408T-A transversion in exon 6, resulting in a phe470-to-ile (F470I) substitution in a conserved residue, and the R417H mutation (603711.0004). Age at onset ranged from 7 to 30 years, and the patients had moderate to severe involvement of the lower extremities with decreased vibratory sense. Mild cerebellar signs, including upper limb dysmetria and saccadic pursuit were observed after long disease duration. One patient had mild upper limb involvement, and 2 had urinary symptoms.

.0008 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, ARG486CYS
SNP: rs116171274, gnomAD: rs116171274, ClinVar: RCV000006481, RCV000197085, RCV000290486, RCV000516130, RCV002476935, RCV003398453

In 2 affected members of a consanguineous Portuguese family with spastic paraplegia-5A (SPG5A; 270800), Goizet et al. (2009) identified a homozygous 1456C-T transition in exon 6 of the CYP7B1 gene, resulting in an arg486-to-cys (R486C) substitution in a highly conserved region. The proband was a 60-year-old woman with onset of spastic paraplegia at age 47 years. She was mild to moderately affected in the lower limbs, with decreased vibratory sensation and urinary symptoms. She also had chronic liver disease with mild elevation of liver enzymes. Liver biopsy showed mild portal and periportal fibrosis with moderate inflammatory infiltration and piecemeal necrosis consistent with unspecific chronic hepatitis. Bile ducts were normal, and there was no cholestasis. Serum samples showed antinuclear antibody, and she was classified as having autoimmune hepatitis, which Goizet et al. (2009) concluded was a fortuitous association and not due to an error in bile acid synthesis. A younger brother had spastic paraplegia, and an elder brother died from cirrhosis of unknown cause at age 40 years.

.0009 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, GLY87VAL
SNP: rs587777221, gnomAD: rs587777221, ClinVar: RCV000106301, RCV002514553

In 2 adult sisters of Italian descent with pure spastic paraplegia-5A (SPG5A; 270800), Arnoldi et al. (2012) identified compound heterozygous mutations in the CYP7B1 gene: a c.260G-T transversion in exon 3, resulting in a gly87-to-val (G87V) substitution at a highly conserved residue, and a c.889G-A transition in exon 4, resulting in a thr297-to-ala (T297A; 603711.0010) substitution. Neither mutation was found in 400 controls. The patients had marked variation in disease severity: 1 had onset at age 10 years of severe lower limb spasticity and developed mild sensory disturbances in the lower limbs, whereas the other had onset of mild spasticity at age 30 years. Brain MRI of both sisters showed similar diffuse white matter abnormalities. Functional studies of the variants were not performed.

.0010 SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE

CYP7B1, THR297ALA
SNP: rs587777222, gnomAD: rs587777222, ClinVar: RCV000106302, RCV000200232, RCV000422978, RCV003415876

For discussion of the thr297-to-ala (T297A) substitution in the CYP7B1 gene that was found in compound heterozygous state in sisters with spastic paraplegia-5A (SPG5A; 270800) by Arnoldi et al. (2012), see 603711.0009.

Goizet et al. (2009) had identified the T297A mutation in 2 unrelated French patients with sporadic pure SPG, one in homozygosity and the other in compound heterozygosity.

.0011 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 3

CYP7B1, ARG112TER
SNP: rs200737038, gnomAD: rs200737038, ClinVar: RCV000206556, RCV000210595, RCV000729706, RCV001312060, RCV001847930

In a Taiwanese infant with congenital bile acid synthesis defect-3 (CBAS3; 613812), Ueki et al. (2008) identified a homozygous c.538C-T transition in exon 3 of the CYP7B1 gene, resulting in an arg112-to-ter (R112X) substitution. The mutation, which was found by exome sequencing of the CYP7B1 and CYP7A1 genes, was present in heterozygous state in the parents. The mutation was not found in 102 controls.

REFERENCES

1. Arnoldi, A., Crimella, C., Tenderini, E., Martinuzzi, A., D'Angelo, M. G., Musumeci, O., Toscano, A., Scarlato, M., Fantin, M., Bresolin, N., Bassi, M. T.Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin. Genet. 81: 150-157, 2012. [PubMed: 21214876] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01624.x\]
2. Biancheri, R., Ciccolella, M., Rossi, A., Tessa, A., Cassandrini, D., Minetti, C., Santorelli, F. M.White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromusc. Disord. 19: 62-65, 2009. [PubMed: 19187859] [Full Text: https://doi.org/10.1016/j.nmd.2008.10.009\]
3. Biddinger, S. B., Haas, J. T., Yu, B. B., Bezy, O., Jing, E., Zhang, W., Unterman, T. G., Carey, M. C., Kahn, C. R.Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nature Med. 14: 778-782, 2008. [PubMed: 18587407] [Full Text: https://doi.org/10.1038/nm1785\]
4. Choi, W.-S., Lee, G., Song, W.-H., Koh, J.-T., Yang, J., Kwak, J.-S., Kim, H.-E., Kim, S. K., Son, Y.-O., Nam, H., Jin, I., Park, Z.-Y., Kim, J., Park, I. Y., Hong, J.-I., Kim, H. A., Chun, C.-H., Ryu, J.-H., Chun, J.-S.The CH25H-CYP7B1-ROR-alpha axis of cholesterol metabolism regulates osteoarthritis. Nature 566: 254-258, 2019. [PubMed: 30728500] [Full Text: https://doi.org/10.1038/s41586-019-0920-1\]
5. Goizet, C., Boukhris, A., Durr, A., Beetz, C., Truchetto, J., Tesson, C., Tsaousidou, M., Forlani, S., Guyant-Marechal, L., Fontaine, B., Guimaraes, J., Isidor, B., and 14 others.CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 132: 1589-1600, 2009. [PubMed: 19439420] [Full Text: https://doi.org/10.1093/brain/awp073\]
6. Hentati, A., Pericak-Vance, M. A., Hung, W.-Y., Belal, S., Laing, N., Boustany, R.-M., Hentati, F., Ben Hamida, M., Siddique, T.Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum. Molec. Genet. 3: 1263-1267, 1994. [PubMed: 7987300] [Full Text: https://doi.org/10.1093/hmg/3.8.1263\]
7. Li-Hawkins, J., Lund, E. G., Turley, S. D., Russell, D. W.Disruption of the oxysterol 7-alpha-hydroxylase gene in mice. J. Biol. Chem. 275: 16536-16542, 2000. [PubMed: 10748048] [Full Text: https://doi.org/10.1074/jbc.M001811200\]
8. Martin, C., Ross, M., Chapman, K. E., Andrew, R., Bollina, P., Seckl, J. R., Habib, F. K.CYP7B generates a selective estrogen receptor beta agonist in human prostate. J. Clin. Endocr. Metab. 89: 2928-2935, 2004. [PubMed: 15181079] [Full Text: https://doi.org/10.1210/jc.2003-031847\]
9. Schule, R., Brandt, E., Karle, K. N., Tsaousidou, M., Klebe, S., Klimpe, S., Auer-Grumbach, M., Crosby, A. H., Hubner, C. A., Schols, L., Deufel, T., Beetz, C.Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics 10: 97-104, 2009. [PubMed: 18855023] [Full Text: https://doi.org/10.1007/s10048-008-0158-9\]
10. Setchell, K. D. R., Schwarz, M., O'Connell, N. C., Lund, E. G., Davis, D. L., Lathe, R., Thompson, H. R., Tyson, R. W., Sokol, R. J., Russell, D. W.Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7-alpha-hydroxylase gene causes severe neonatal liver disease. J. Clin. Invest. 102: 1690-1703, 1998. [PubMed: 9802883] [Full Text: https://doi.org/10.1172/JCI2962\]
11. Tsaousidou, M. K., Ouahchi, K., Warner, T. T., Yang, Y., Simpson, M. A., Laing, N. G., Wilkinson, P. A., Madrid, R. E., Patel, H., Hentati, F., Patton, M. A., Hentati, A., Lamont, P. J., Siddique, T., Crosby, A. H.Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82: 510-515, 2008. [PubMed: 18252231] [Full Text: https://doi.org/10.1016/j.ajhg.2007.10.001\]
12. Ueki, I., Kimura, A., Nishiyori, A., Chen, H.-L., Takei, H., Nittono, H., Kurosawa, T.Neonatal cholestatic liver disease in an Asian patient with a homozygous mutation in the oxysterol 7-alpha-hydroxylase gene. J. Pediat. Gastroent. Nutr. 46: 465-469, 2008. [PubMed: 18367963] [Full Text: https://doi.org/10.1097/MPG.0b013e31815a9911\]
13. Wilkinson, P. A., Crosby, A. H., Turner, C., Patel, H., Wood, N. W., Schapira, A. H., Warner, T. T.A clinical and genetic study of SPG5A linked to autosomal recessive hereditary spastic paraplegia. Neurology 61: 235-238, 2003. [PubMed: 12874406] [Full Text: https://doi.org/10.1212/01.wnl.0000069920.42968.8d\]

Contributors:

Hilary J. Vernon - updated : 03/09/2021
Ada Hamosh - updated : 05/22/2019
Cassandra L. Kniffin - updated : 3/18/2014
Cassandra L. Kniffin - updated : 3/31/2010
Cassandra L. Kniffin - updated : 10/27/2009
Cassandra L. Kniffin - updated : 5/14/2009
Marla J. F. O'Neill - updated : 7/25/2008
Cassandra L. Kniffin - updated : 4/18/2008
John A. Phillips, III - updated : 7/21/2006
Dawn Watkins-Chow - updated : 6/7/2001
Dawn Watkins-Chow - updated : 6/6/2001

Creation Date:

Victor A. McKusick : 4/8/1999

Edit History:

carol : 10/13/2023
carol : 03/09/2021
carol : 08/20/2020
alopez : 05/22/2019
alopez : 02/21/2017
carol : 02/15/2017
carol : 03/21/2014
carol : 3/20/2014
mcolton : 3/18/2014
ckniffin : 3/18/2014
carol : 3/15/2011
wwang : 4/6/2010
ckniffin : 3/31/2010
wwang : 11/16/2009
ckniffin : 10/27/2009
wwang : 5/21/2009
ckniffin : 5/14/2009
wwang : 7/28/2008
terry : 7/25/2008
wwang : 4/24/2008
ckniffin : 4/18/2008
alopez : 7/21/2006
carol : 6/14/2006
ckniffin : 6/6/2006
carol : 6/7/2001
carol : 6/6/2001
alopez : 6/3/1999
carol : 4/8/1999
carol : 4/8/1999
carol : 4/8/1999
carol : 4/8/1999