GeneBe

AKR1D1

protein-coding

aldo-keto reductase family 1 member D1, the group of Aldo-keto reductases

Gene summary

The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

Previous symbols:
  • SRD5B1

MANE transcript

NM_005989.4

Inheritance

AR

ClinVar variants

P:37U:85B:21

Top phenotype

Bile acid synthesis defect, congenital, 2

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr7:138,002,324-138,118,305

External References & Databases

Ensembl (ENSG00000122787)NCBI Gene (6718)OMIM (604741)HGNC:388GenCCUniProt (P51857)AlphaFoldClinVar (AKR1D1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~116.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital bile acid synthesis defect 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009339

Submitter: PanelApp Australia

congenital bile acid synthesis defect 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009339

Submitter: Labcorp Genetics (formerly Invitae)

congenital bile acid synthesis defect 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009339

Submitter: ClinGen

The gene *AKR1D1* has been definitively associated with the disease Congenital Bile Acid Synthesis Defect 2 according to the gene–disease association criteria of the ACMG (SOP version 11). This disease results from an anomaly of bile acid synthesis and is characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins. Homozygous or compound heterozygous mutations in the AKR1D1 gene cause this disease. Mutations in *AKR1D1* cause congenital bile acid synthesis defect type 2 by impairing the enzyme 3-oxo-5-β-steroid 4-dehydrogenase. This enzyme, crucial for bile acid production, is responsible for the NADPH-dependent conversion of 5beta-cholestan-3-one to cholest-4-en-3-one. Impaired conversion leads to abnormal bile acids, cholesterol buildup, and fat-soluble vitamin deficiencies (PMID: 30809085). The AKR1D1 enzyme's biochemical disruptions were initially identified using FAB-MS, revealing high 3-oxo-Δ4 bile acids and low normal bile acid conjugates in urine (PMID: 1735522). Affected infants present with symptoms of jaundice, failure to thrive, and steatorrhea. Timely diagnosis is vital because the liver disease associated with this condition can be life-threatening (it can lead to cirrhosis and death), yet it can be managed with oral primary bile acid replacement (PMID: 30809085). **Summary of Case Level Data (10.2 points)**: 10 probands were scored with 7 variants (2 frameshift, 1 nonsense, 5 missense) from 4 publications (PMID: 23679950, 35758383, 12970144, 23323017). **Summary of Experimental Evidence (2.5 points)**: AKR1D1 knockout mice indicated sex-specific metabolic alterations. Male knockout mice had enhanced insulin sensitivity and decreased lipid buildup in the liver and adipose tissue, but had higher triglyceride levels and intramuscular triacylglycerol. These findings underline AKR1D1's important function in regulating bile acid synthesis and metabolic balance in a sex-specific way. (PMID: 35318963). Another study characterized AKR1D1 mutations. Clinically relevant mutants showed reduced activity, decreased stability, and heightened thermolability. One mutant (P133R) exhibited uncompetitive kinetics and lower catalytic efficiency, compromising bile acid synthesis and leading to potential bile acid deficiency syndromes ​(PMID: 20522910). In summary, experimental and clinical evidence consistently supports a definitive gene-disease association between AKR1D1 and autosomal recessive congenital bile acid synthesis defect due to AKR1D1. This classification was approved by the ClinGen IEM GCEP on September 22, 2024 (SOP Version 11).

congenital bile acid synthesis defect 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009339

Submitter: G2P

congenital bile acid synthesis defect 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009339

Submitter: Orphanet

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 2AR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: Early interventions, such as bile replacement therapy, can be beneficial, though liver transplant may be necessary in severe cases

Refs: 2897546; 3198770; 2072042; 2248502; 8707100; 12970144; 15030995; 20522910; 23160874Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AKR1D1 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 65
AKR1D1-related disorderTotal: 52
Congenital bile acid synthesis defect 2Total: 42
Inborn genetic diseasesTotal: 40
not specifiedTotal: 10
Congenital bile acid synthesis defectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005989.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
19
clinvar
1
clinvar
 25
missense
2
clinvar
10
clinvar
77
clinvar
1
clinvar
 90
nonsense
2
clinvar
8
clinvar
1
clinvar
 11
start loss
0
frameshift
4
clinvar
4
clinvar
 8
splice donor/acceptor (+/-2bp)
7
clinvar
2
clinvar
 9
Total82985201143

Highest pathogenic variant AF is 0.00011649248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005989.4RefSeqNP_005980.19MANE Select
ENST00000242375.8EnsemblENSP00000242375.39MANE Select
NM_001190906.2RefSeqNP_001177835.18Standard
NM_001190907.2RefSeqNP_001177836.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Steroid hormone biosynthesis - Homo sapiens (human)
  • Primary bile acid biosynthesis - Homo sapiens (human)
  • 27-Hydroxylase Deficiency
  • 17-Beta Hydroxysteroid Dehydrogenase III Deficiency
  • Bile Acid Biosynthesis

Biological Process

  • bile acid biosynthetic process
  • cholesterol catabolic process
  • digestion
  • steroid metabolic process
  • C21-steroid hormone metabolic process

Molecular Function

  • alditol:NADP+ 1-oxidoreductase activity
  • aldo-keto reductase (NADP) activity
  • steroid binding
  • alcohol dehydrogenase (NADP+) activity
  • steroid dehydrogenase activity

Cellular Component

  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000242375
Coding exons
9
Length
115663
Individuals with no LoFs
125694
Homozygous LoFs
0
Heterozygous LoFs
54
Defined
125748
p
0.000215
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1721751820.9640.000009852153
Missense (PolyPhen)6979.110.8722955
Synonymous-0.6626962.41.110.00000317599
Loss of Function1.151318.30.7099.50e-7214

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000140.00012rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000330.00032rare
South Asian0.000250.00023rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Efficiently catalyzes the reduction of progesterone, androstenedione, 17-alpha-hydroxyprogesterone and testosterone to 5-beta-reduced metabolites. The bile acid intermediates 7- alpha,12-alpha-dihydroxy-4-cholesten-3-one and 7-alpha-hydroxy-4- cholesten-3-one can also act as substrates. {ECO:0000269|PubMed:11342103}.;

Recessive Scores

pRec
0.168

Intolerance Scores

LoFtool
0.937
RVIS EVS
-0.65
RVIS percentile EVS
16.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.943

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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