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AKR1D1
aldo-keto reductase family 1 member D1
AKR1D1 encodes an enzyme that catalyses a critical step in bile acid synthesis, enabling proper digestion and absorption of fats. The AKR1D1 gene provides instructions for producing an enzyme called 5-beta-steroid reductase, which operates within liver cells to facilitate bile acid production.
AKR1D1 is located on the long (q) arm of chromosome 7, at band 7q33. Arm ratio per GRCh38 - banding schematic.
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Overview
AKR1D1 is located on chromosome 7 and belongs to the aldo-keto reductase enzyme superfamily. The encoded protein plays an indispensable role in converting cholesterol into bile acids through a multi-step biochemical pathway. Without functional AKR1D1 enzyme activity, the liver cannot produce adequate amounts of normal bile acids, which impairs digestion and allows toxic bile acid precursors to accumulate.
Pathogenic variants in AKR1D1 are associated with congenital bile acid synthesis defect type 2, a rare metabolic disorder characterised by cholestasis beginning in infancy or early childhood. The gene is included on multiple NHS Genomic Medicine Service panels related to cholestatic liver disease and inborn errors of metabolism, reflecting its clinical importance in diagnosing unexplained liver dysfunction in young children.
What the gene does
The AKR1D1 gene encodes 5-beta-steroid reductase, also known as 3-oxo-5-beta-steroid 4-dehydrogenase, an enzyme that catalyses the reduction of the delta-4 double bond in steroid intermediates. This enzyme is expressed predominantly in hepatocytes, where it participates in the bile acid biosynthesis pathway that converts cholesterol into the primary bile acids cholic acid and chenodeoxycholic acid.
Specifically, the AKR1D1 enzyme performs the third biochemical transformation in this pathway, converting 7-alpha-hydroxy-4-cholesten-3-one into 7-alpha-hydroxy-5-beta-cholesten-3-one. This reaction is essential for creating the characteristic saturated ring structure found in mature bile acids. The resulting bile acids facilitate the emulsification and absorption of dietary fats and fat-soluble vitamins in the small intestine, whilst also serving as signalling molecules that regulate cholesterol homeostasis and glucose metabolism throughout the body.
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Chromosome location
AKR1D1 is positioned on the long arm of chromosome 7 at cytogenetic band 7q33. The encoded protein comprises 326 amino acids. The gene structure and regulatory elements ensure expression is concentrated in hepatic tissue, where bile acid synthesis primarily occurs.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The AKR1D1 enzyme belongs to the aldo-keto reductase superfamily, members of which typically adopt a characteristic alpha-beta barrel fold that accommodates NADPH cofactor binding and creates the active site for steroid substrate recognition. The enzyme functions as a monomer and requires NADPH as an electron donor to carry out the reduction reaction on steroid intermediates.
Key variants
More than ten pathogenic variants in AKR1D1 have been identified in individuals with congenital bile acid synthesis defect type 2. Most reported variants are missense changes that substitute individual amino acids within the enzyme, impairing its catalytic efficiency or stability. These alterations result in markedly reduced or absent enzyme activity, preventing normal bile acid formation and leading to accumulation of atypical steroid metabolites that can be detected in urine.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.148C>T | p.Arg50Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital bile acid synthesis defect 2 |
c.583G>T | p.Glu195Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital bile acid synthesis defect 2 |
c.781C>T | p.Arg261Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital bile acid synthesis defect |
c.796C>T | p.Arg266Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital bile acid synthesis defect 2 |
c.797G>A | p.Arg266Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital bile acid synthesis defect 2 |
c.238del | p.Glu80fs | Pathogenic | ★☆☆☆ | Congenital bile acid synthesis defect 2 |
c.267G>A | p.Trp89Ter | Pathogenic | ★☆☆☆ | Congenital bile acid synthesis defect 2 |
c.350dup | p.Tyr117Ter | Pathogenic | ★☆☆☆ | not provided |
c.580-13T>A | - | Pathogenic | ★☆☆☆ | Congenital bile acid synthesis defect 2 |
c.316C>T | p.Leu106Phe | Pathogenic | - | Congenital bile acid synthesis defect 2 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in AKR1D1 cause congenital bile acid synthesis defect type 2, a rare autosomal recessive disorder. Affected individuals typically present in infancy or early childhood with cholestasis, characterised by impaired bile flow from the liver. Clinical features may include jaundice, poor weight gain, fat-soluble vitamin deficiencies, and progressive liver damage if untreated. Early biochemical diagnosis through urine steroid profiling allows initiation of bile acid replacement therapy, which can prevent or reverse liver injury in many cases.
No disease links recorded for this gene in our reference set.
UK clinical status
AKR1D1 holds green classification status on several NHS Genomic Medicine Service panels, including Cholestasis, Neonatal Cholestasis, Likely Inborn Error of Metabolism, and Undiagnosed Metabolic Disorders. This classification indicates strong evidence supporting the gene's role in these clinical presentations. Sequencing of AKR1D1 is recommended for infants and children presenting with unexplained cholestasis, particularly when routine causes have been excluded and urine metabolite screening suggests a bile acid synthesis defect.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is AKR1D1 deficiency diagnosed?
Diagnosis typically involves urine steroid profiling by gas chromatography-mass spectrometry, which reveals characteristic abnormal bile acid precursors. Confirmatory molecular genetic testing identifies pathogenic variants in both copies of the AKR1D1 gene.
Can AKR1D1-related cholestasis be treated?
Primary bile acid replacement therapy with cholic acid can bypass the enzymatic defect, suppressing production of toxic metabolites and often reversing liver injury when initiated early. Treatment is generally lifelong and requires monitoring by metabolic specialists.
What inheritance pattern does AKR1D1 follow?
Congenital bile acid synthesis defect type 2 is inherited in an autosomal recessive manner, meaning affected individuals carry pathogenic variants in both gene copies. Parents are typically unaffected carriers with one working gene copy.
References
- Chen M, Penning TM. 5β-Reduced steroids and human Δ(4)-3-ketosteroid 5β-reductase (AKR1D1). Steroids. 2014. PMID: 24513054
- Jin Y, Chen M, Penning TM. Rate of steroid double-bond reduction catalysed by the human steroid 5β-reductase (AKR1D1) is sensitive to steroid structure: implications for steroid metabolism and bile acid synthesis. The Biochemical journal. 2014. PMID: 24894951
- Mindnich R, Drury JE, Penning TM. The effect of disease associated point mutations on 5β-reductase (AKR1D1) enzyme function. Chemico-biological interactions. 2011. PMID: 21185810
- Lemonde HA, Custard EJ, Bouquet J. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003. PMID: 12970144