*604741	Links
ALDO-KETO REDUCTASE FAMILY 1, MEMBER D1; AKR1D1

Alternative titles; symbols

DELTA(4)-3-OXOSTEROID 5-BETA-REDUCTASE
STEROID 5-BETA-REDUCTASE; SRD5B1
5-@BETA-REDUCTASE

TEXT

DESCRIPTION

Human delta(4)-3-oxosteroid 5-beta-reductase (steroid 5-beta-reductase) catalyzes 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure.

CLONING

Kondo et al. (1994) screened a human liver cDNA library with a rat 5-beta-reductase cDNA to isolate the cDNA encoding human 5-beta-reductase. The full-length cDNA encodes a peptide of 326 amino acids with a relative mass of 37,380 Da. Northern blot analysis of human liver RNA identified a 2.7-kb transcript. The authors inserted the 5-beta-reductase cDNA into an expression vector and transfected it into COS cells. The recombinant protein was detected by immunoblot analysis using a monoclonal antibody against rat 5-beta-reductase. Recombinant 5-beta-reductase showed 5-beta-reductase activity against several substrates, as detected by high-performance liquid chromatography.

MAPPING

Charbonneau and Luu-The (1999) used FISH analysis to map SRD5B1, the gene encoding human 5-beta-reductase, to chromosome 7q32-q33 and a pseudogene (SRD5BP1) to 1q23-q25.

MOLECULAR GENETICS

In 3 unrelated patients with neonatal cholestasis due to delta(4)-3-oxosteroid 5-beta-reductase deficiency (CBAS2; 235555), Lemonde et al. (2003) identified 3 different homozygous mutations in the AKR1D1 gene (604741.0001-604741.0003). Urinary profile of all 3 patients showed almost complete absence of chenodeoxycholic and cholic acids.

ALLELIC VARIANTS
(selected examples)

.0001 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2 [AKR1D1, PRO198LEU ]

In a patient with intrahepatic cholestasis due to delta(4)-3-oxosteroid 5-beta-reductase deficiency (235555) first reported by Clayton et al. (1996), Lemonde et al. (2003) identified a homozygous 662C-T mutation in the AKR1D1 gene, resulting in a pro198-to-leu (P198L) substitution. The mutation was not identified in 100 control chromosomes. The mutation is predicted to interfere with normal NADPH binding, rendering the mutant enzyme inactive.

.0002 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2 [AKR1D1, 1-BP DEL, 511T ]

In a Pakistani patient with CBAS2 (235555), born of consanguineous parents, Lemonde et al. (2003) identified a homozygous 1-bp deletion (511delT) in the AKR1D1 gene, resulting in a frameshift and premature truncation of the protein in exon 5. The mutation was not identified in 100 control chromosomes.

.0003 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 2 [AKR1D1, LEU106PHE ]

In a patient from Sri Lanka with CBAS2 (235555), whose parents were consanguineous, Lemonde et al. (2003) identified a homozygous 385C-T transition in the AKR1D1 gene, resulting in a leu106-to-phe (L106F) substitution within the alpha-3 helix of the enzyme. The mutation was not identified in 100 control chromosomes.

REFERENCES

1. Charbonneau, A.; Luu-The, V. :

Assignment of steroid 5-beta-reductase (SRD5B1) and its pseudogene (SRD5BP1) to human chromosome bands 7q32-q33 and 1q23-q25, respectively, by in situ hybridization. Cytogenet. Cell Genet. 84: 105-106, 1999.
PubMed ID : 10343119

2. Clayton, P. T.; Mills, K. A.; Johnson, A. W.; Barabino, A.; Marazzi, M. G. :

Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid. Gut 38: 623-628, 1996.
PubMed ID : 8707100

3. Kondo, K.-H.; Kai, M.-H.; Setoguchi, Y.; Eggertsen, G.; Sjoblom, P.; Setoguchi, T.; Okuda, K.-I.; Bjorkhem, I. :

Cloning and expression of cDNA of human delta(4)-3 oxosteroid 5-beta-reductase and substrate specificity of the expressed enzyme. Europ. J. Biochem. 219: 357-363, 1994.
PubMed ID : 7508385

4. Lemonde, H. A.; Custard, E. J.; Bouquet, J.; Duran, M.; Overmars, H.; Scambler, P. J.; Clayton, P. T. :

Mutations in SRD5B1 (AKR1D1), the gene encoding delta-4-3-oxosteroid 5-beta-reductase, in hepatitis and liver failure in infancy. Gut 52: 1494-1499, 2003.
PubMed ID : 12970144

CONTRIBUTORS

Cassandra L. Kniffin - updated : 6/6/2006

CREATION DATE

Stefanie A. Nelson : 3/24/2000

EDIT HISTORY

carol : 6/14/2006
ckniffin : 6/6/2006
alopez : 3/24/2000
alopez : 3/24/2000

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