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Mutations in SRD5B1 ( AKR1D1 ), the gene encoding Δ 4 -3-oxosteroid 5β-reductase, in hepatitis and liver failure in infancy
Open accessAbstract
BACKGROUND: A substantial group of patients with cholestatic liver disease in infancy excrete, as the major urinary bile acids, the glycine and taurine conjugates of 7alpha-hydroxy-3-oxo-4-cholenoic acid and 7alpha,12alpha-dihydroxy-3-oxo-4-cholenoic acid. It has been proposed that some (but not all) of these have mutations in the gene encoding delta(4)-3-oxosteroid 5beta-reductase (SRD5B1; AKR1D1, OMIM 604741). AIMS: Our aim was to identify mutations in the SRD5B1 gene in patients in whom chenodeoxycholic acid and cholic acid were absent or present at low concentrations in plasma and urine, as these seemed strong candidates for genetic 5beta-reductase deficiency. PATIENTS AND SUBJECTS: We studied three patients with neonatal onset cholestatic liver disease and normal gamma-glutamyl transpeptidase in whom 3-oxo-delta(4) bile acids were the major bile acids in urine and plasma and saturated bile acids were at low concentration or undetectable. Any base changes detected in SRD5B1 were sought in the parents and siblings and in 50 ethnically matched control subjects. METHODS: DNA was extracted from blood and the nine exons of SRD5B1 were amplified and sequenced. Restriction enzymes were used to screen the DNA of parents, siblings, and controls. RESULTS: Mutations in the SRD5B1 gene were identified in all three children. Patient MS was homozygous for a missense mutation (662 C>T) causing a Pro198Leu amino acid substitution; patient BH was homozygous for a single base deletion (511 delT) causing a frame shift and a premature stop codon in exon 5; and patient RM was homozygous for a missense mutation (385 C>T) causing a Leu106Phe amino acid substitution. All had liver biopsies showing a giant cell hepatitis; in two, prominent extramedullary haemopoiesis was noted. MS was cured by treatment with chenodeoxycholic acid and cholic acid; BH showed initial improvement but then deteriorated and required liver transplantation; RM had advanced liver disease when treatment was started and also progressed to liver failure. CONCLUSIONS: Analysis of blood samples for SRD5B1 mutations can be used to diagnose genetic 5beta-reductase deficiency and distinguish these patients from those who have another cause of 3-oxo-delta(4) bile aciduria, for example, severe liver damage. Patients with genetic 5beta-reductase deficiency may respond well to treatment with chenodeoxycholic acid and cholic acid if liver disease is not too advanced.
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“Inherited mutations in AKR1D1 have been studied in patients with bile-acid deficiency that develops in infants and is characterized by reduced formation of bile acids and accumulation of Δ4-3-keto and 5α-reduced (allo-bile acids) which are hepatotoxic.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [95]
In the citing paper
“seven point mutations have been identified in patients with 5β-reductase deficiency: Leu106Phe, Pro133Arg, Gly223Glu, Pro198Leu, Asp241Val, Arg261Cys and Arg266Glu [95–97, 99, 100].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [95]
In the citing paper
“This deficiency is exacerbated by the inability to from sufficient bile acids to feed-back and inhibit the rate determining step in the pathway, 7α-hydroxylase (CYP7A1), and thus the formation of allo-bile acids will be further elevated [95–99].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [95]
In the citing paper
“So far SNPs in AKR1C1, AKR1C2 and AKR1C4 have been studied at the protein level and Phe46Tyr has been associated with disease [95–97, 99, 103, 104].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [95]
In the citing paper
“Mutations of AKR1D1 lead to severely reduced to completely absent urinary 5β-reduced steroid excretion and hepatic failure, as AKR1D1 is essentially involved in hepatic bile acid synthesis, but no other clinical manifestations (Gonzales et al., 2004, Lemonde et al., 2003, Palermo et al., 2008).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Lemonde et al., 2003
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Cites
Nuclear Receptors and the Control of Metabolism
Francis, G. A., Fayard, E., Picard, F., & Auwerx, J. H. (2003) · Annual Review of Physiology · doi:10.1146/annurev.physiol.65.092101.142528 · Cited by 647
Comparative anatomy of the aldo–keto reductase superfamily
Jez, J. M., BENNETT, M. J., Schlegel, B. P., Lewis, M., & Penning, T. M. (1997) · Biochemical Journal · doi:10.1042/bj3260625 · Cited by 603
BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis
Edwards, P. A., Kast-Woelbern, H. R., & Anisfeld, A. M. (2002) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)30180-2 · Cited by 387
Setchell, K. D., Schwarz, M., O'Connell, N. C., Lund, E. G., Davis, D. L., Lathe, R., Thompson, H. R., Weslie Tyson, R., Sokol, R. J., & Russell, D. W. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2962 · Cited by 375
Peroxisome biogenesis disorders
Gould, S. J., & Valle, D. L. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02056-4 · Cited by 354
Control of messenger RNA stability in higher eukaryotes
Ross, J. (1996) · Trends in Genetics · doi:10.1016/0168-9525(96)10016-0 · Cited by 313
Setchell, K. D. R., Suchy, F. J., Welsh, M. B., Zimmer-Nechemias, L., Heubi, J. E., & Balistreri, W. F. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113837 · Cited by 254
Cui, J., Huang, L., Zhao, A., Lew, J.-L., Yu, J., Sahoo, S. P., Meinke, P. T., Royo, I., Peláez, F., & Wright, S. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209323200 · Cited by 247
Clayton, P. T., Leonard, J. V., Lawson, A. M., Setchell, K. D. R., Andersson, S., Egestad, B., & Sjövall, J. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112915 · Cited by 216
Self-citationSetchell, K. D. R., Heubi, J. E., Bove, K. E., O’Connell, N. C., Brewsaugh, T., Steinberg, S. J., Moser, A. B., & Squires, R. H. (2003) · Gastroenterology · doi:10.1053/gast.2003.50017 · Cited by 175
Flagged first, then by citations
Research works printed but not linked: 6
- 1988, Lancet, 1, 1283
- 1997, Lancet, 349, 329
- Lemonde HA. A study using tandem mass spectrometry and molecular biological techniques to facilitate the diagnosis of inborn errors of bile acid synthesis, with particular reference to Δ 4 -3-oxosteroid 5β-reductase deficiency, PhD thesis. London: University of London, 2000.
- 10.1042/BST0290298 · DOI
- 1991, J Pediatr Gastroenterol Nutr, 12, 383
- 1996, Hepatology, 23, 115
Cited by
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Setchell, K. D. R., Zhao, X., Reed, S., & Zhang, W. (2026) · Metabolites · doi:10.3390/metabo16070436 · Cited by 1
Setchell, K. D. R., & Kohli, R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-37591-7.00002-1 · Cited by 1
Parajuli, B. (2014) · IUScholarWorks (Indiana University) · doi:10.7912/c2/1848 · Cited by 1
Rare Cholesterol Related Disorders – A Sterolomic Library for Diagnosis and Monitoring of DiseasesPreprint
Asgari, M. A., Yutuc, E., Abdel‐Khalik, J., Crick, P. J., Morris, A. A. M., Jones, S. A., Ghosh, A., Curnock, R., Hart, C., Schöls, L. J., et al. (2025) · medRxiv · doi:10.1101/2025.06.23.25328695 · Cited by 1
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) during liver regeneration
Setchell, K. D. R., Suchy, F. J., Mb, W., Zimmer-Nechemias, L., Heubi, J. E., Ra, C., Sumazaki, R., Nakamura, N., Shoda, J., Kurosawa, T., et al. (2004)
Co nowego w cholestazie – część 3. Wrodzone zaburzenia syntezy kwasów żółciowych
Lipiński, P., Socha, P., & Jankowska, I. (2017) · Pediatria Polska · doi:10.1016/j.pepo.2017.03.013
Disorders of Bile Acid Synthesis and Metabolism in Children
Setchell, K. D. R., & Heubi, J. E. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108918978.033
Adolf Windaus Prize Lecture 2004
Setchell, K. D. R. (2007) · Springer eBooks · doi:10.1007/1-4020-2913-6_2
Disorders of Bile Acid Synthesis
Clayton, P. T. (2006) · Springer eBooks · doi:10.1007/3-540-28962-3_34
Self-citationThe Aldo-Keto Reductase Superfamily
Penning, T. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00010-3
Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns
Bittmann, S. (2024) · Asian Journal of Pediatric Research · doi:10.9734/ajpr/2024/v14i5340
Glucocorticoid metabolism and activation
Othonos, N., & Tomlinson, J. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13825-6.00210-7
El-Koofy, N. M., Elgebaly, H. F., & Elmonem, M. A. (2025) · Egyptian Pediatric Association Gazette · doi:10.1186/s43054-025-00386-3
Thio, J., Ajmera, A., Ouyang, J., & Benabe, S. H. (2025) · BMJ Case Reports · doi:10.1136/bcr-2025-266785
Hudson, J., Hyunh, S., Rakić, B., & Boerkoel, C. F. (2025) · American Journal of Medical Genetics Part A · doi:10.1002/ajmga.70025
Gardin, A., Ruiz, M., Beime, J., Cananzi, M., Rathert, M., Rohmer, B., Grabhorn, E. F., Almes, M., Logarajah, V., Peña-Quintana, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24770249
Izquierdo-Martínez, A., Rubio-Prieto, J. L., Rodriguez-Rodriguez, A., Martínez-Martos, Z., & Delgado‐Pecellín, C. (2026) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2026.111151
Gardin, A., Laborde, N., & Gonzales, E. M. (2026) · Perfectionnement en Pédiatrie · doi:10.1016/s2588-932x(26)00173-7
Lagrine, M., Kaouani, D., Qadiry, R. E., Nassih, H., Abourrahouat, A., & Aitsab, I. (2026) · Cureus · doi:10.7759/cureus.116257
Bile Acid Synthesis and Metabolism Disorders
Mysore, K. R., Kohli, R., & Setchell, K. D. R. (2026) · Clinics in Liver Disease · doi:10.1016/j.cld.2026.08.004
Genetic hepatocellular cholestasis: an update
Gardin, A., Pouillot, W., Almes, M., Mussini, C., Gonzales, E. M., & Jacquemin, E. (2026) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2026.102939
Zhu, H., Chen, H., Gong, Q., Chen, Z., Zhang, C., Xu, J., & Wang, T. (2026) · Medicinal Research Reviews · doi:10.1002/med.70116
Metadata
- Authors
- Lemonde, H. A., Custard, E. J., Bouquet, J., Duran, M., Overmars, H., Scambler, P. J., & Clayton, P. T.
- Affiliations
- Great Ormond Street Hospital (GB)
- Erasmus MC - Sophia Children’s Hospital (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Clayton, P T
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2003-09-11
- Volume
- 52
- Issue
- 10
- Pages
- 1494-1499
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC1773813
- OpenAlex
- W2020121378
- Cited by
- 125
- References
- 41
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 8 · 2017: 10 · 2016: 6 · 2015: 4 · 2014: 7 · 2013: 7 · 2012: 5
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Engineering and Physical Sciences Research Council
- Topics
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- AKR1D1, cholestatic liver disease, neonatal liver failure, giant cell hepatitis, extramedullary hematopoiesis, chenodeoxycholic acid, cholic acid, liver transplantation
- MeSH terms
- Chenodeoxycholic Acid, DNA Mutational Analysis, Female, Hepatitis, Humans, Infant, Newborn, Liver, Male, Oxidoreductases, Polymerase Chain Reaction, Liver Failure, Gene Deletion, Cholic Acid, Mutation, Missense, Spectrometry, Mass, Electrospray Ionization
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