Mutations in SRD5B1 (AKR1D1), the gene encoding  4-3-oxosteroid 5 -reductase, in hepatitis and liver failure in infancy

Abstract

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 7a-hydroxy-3-oxo-4-cholenoic acid and 7a,12a-dihydroxy-3-oxo-4-cholenoic acid. It has been proposed that some (but not all) of these have mutations in the gene encoding D 4 -3-oxosteroid 5b-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 5b-reductase deficiency. Patients and subjects: We studied three patients with neonatal onset cholestatic liver disease and normal c-glutamyl transpeptidase in whom 3-oxo-D 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 5b-reductase deficiency and distinguish these patients from those who have another cause of 3-oxo-D 4 bile aciduria, for example, severe liver damage. Patients with genetic 5b-reductase deficiency may respond well to treatment with chenodeoxycholic acid and cholic acid if liver disease is not too advanced.

Genetic Variation in Aldo-Keto Reductase 1D1 (AKR1D1) Affects the Expression and Activity of Multiple Cytochrome P450s

“…AKR1D1 genetic variations were also reported in three patients with neonatal onset cholestatic liver disease. These patients had rare disease causing AKR1D1 genetic variation that was not detected in 100 chromosomes of control individuals indicating that these are disease-specific mutations (Lemonde et al, 2003). Our study did identify a common 39-UTR SNP (rs1872930) genotype that correlated significantly with total hepatic AKR1D1 and P450 mRNA expression.…”

“…In addition, we tested whether genetic variation in AKR1D1 was associated with P450 mRNA expression and activity. To date, genetic variation in AKR1D1 has not been explored in normal individuals, and rare genetic variants have been reported only in infants that lack cholic acid and chenodeoxycholic acid (Lemonde et al, 2003). In this study, we report that genetic variation in AKR1D1 contributes to the observed variation in P450 expression and activity of the P450 liver network.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…The resulting 5β-dihydrosteroids are further reduced by liver AKR1C4 to ultimately form chenodeoxycholic and cholic acids. Mutations in the gene encoding AKR1D1 (also known as SRD5B1) in human patients lead to neonatal cholestasis, hepatitis, and liver failure (Lemonde et al, 2003;Setchell et al, 1988). AKR1D1 also exhibit enzymatic activity for several steroid hormones including testosterone, progesterone, cortisol and cortisone among others (Okuda and Okuda, 1984) and is present in the brain (Hutchison and Steimer, 1981) and in tissues of the genitourinary tract.…”

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

“…The letters used are based on order of discovery. The number of non-synonymous SNPs in the coding regions of human AKRs so far reported are listed in parenethesis: AKR1A1 (2); AKR1B1 (8); AKR1B10 (3); AKR1C1 (3); AKR1C2 (10); AKR1C3 (9); AKR1C4 (5); AKR1D1 (although none are listed, inherited mutations are associated with bile acid deficiency [109][110][111][112]); AKR7A2 (8) and AKR7A3 (3). Since the crystal structures of many of these AKRs are available these SNPs can be mapped to these structures to predict their functional consequences.…”