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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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“Mutations of AKR1D1 lead to severely reduced to completely absent urinary 5b-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).”
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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