SRD5B1 gene analysis needed for the accurate diagnosis of primary 3‐oxo‐Δ4‐steroid 5β‐reductase deficiency
Abstract
BACKGROUND AND AIM: We encounter hyper-3-oxo-Delta(4) bile aciduria in patients with severe cholestatic liver disease or fulminant liver failure during the neonatal period. However, simply by bile acid analysis, it is difficult to distinguish hyper-3-oxo-Delta(4) bile aciduria from primary 3-oxo-Delta(4)-steroid 5beta-reductase deficiency. METHODS: To determine whether 3-oxo-Delta(4)-steroid 5beta-reductase (SRD5B1) gene analysis is required for the accurate diagnosis of 3-oxo-Delta(4)-steroid 5beta-reductase deficiency, we evaluated the laboratory data, bile acid analysis and SRD5B1 gene analysis from six patients with hyper-3-oxo-Delta(4) bile aciduria. RESULTS: Based upon the results, four patients who had developed neonatal liver failure were diagnosed as having neonatal hemochromatosis. Two patients with chronic cholestasis were diagnosed as having primary 3-oxo-Delta(4)-steroid 5beta-reductase deficiency by SRD5B1 gene analysis. The SRD5B1 gene in these two patients had a heterozygous mutation, G737A (Gly 223 Glu) in one patient and C217T (Arg 50 stop) in the other. CONCLUSIONS: Based upon our limited data, we conclude that SDR5B1 gene analysis is required for the accurate diagnosis of 3-oxo-Delta(4)-steroid 5beta-reductase deficiency. Moreover, we think that it is important to elucidate whether there is a heterozygous or a compound heterozygous mutation of the SRD5B1 gene in our two patients.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Inherited AKR1D1 mutations cause bile-acid deficiency in infants characterized by reduced bile acid formation and accumulation of hepatotoxic Δ4-3-keto and 5α-reduced allo-bile acids.
“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 [97]
The deficiency is exacerbated by inability to form sufficient bile acids to feedback-inhibit CYP7A1, leading to further elevation of allo-bile acids.
“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 [97]
SNPs in AKR1C1, AKR1C2, and AKR1C4 have been studied at the protein level, and Phe46Tyr has been associated with disease.
“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 [97]
Seven point mutations are known in patients with 5β-reductase deficiency: Leu106Phe, Pro133Arg, Gly223Glu, Pro198Leu, Asp241Val, Arg261Cys, and Arg266Glu.
“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 [97]
Cites
Setchell, K. D. R., Suchy, F. J., Welsh, M. B., Zimmer-Nechemias, L., Heubi, J. E., & Balistreri, W. F. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113837 · Cited by 254 · see citing works
KONDO, K., KAI, M., SETOGUCHI, Y., EGGERTSEN, G., SJÖBLOM, P., SETOGUCHI, T., OKUDA, K., & BJÖRKHEM, I. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.tb19947.x · Cited by 139 · see citing works
Lemonde, H. A., Custard, E. J., Bouquet, J., Duran, M., Overmars, H., Scambler, P. J., & Clayton, P. T. (2003) · Gut · doi:10.1136/gut.52.10.1494 · Cited by 125 · see citing works
Δ4-3-Oxosteroid 5β-reductase deficiency causing neonatal liver failure and hemochromatosis
Shneider, B. L., Setchell, K. D. R., Whitington, P. F., Neilson, K. A., & Suchy, F. J. (1994) · The Journal of Pediatrics · doi:10.1016/s0022-3476(94)70310-8 · Cited by 118 · see citing works
Fetal and infantile hemochromatosis†
Whitington, P. F. (2006) · Hepatology · doi:10.1002/hep.21129 · Cited by 108 · see citing works
Daugherty, Y. C., Setchell, K. D. R., Heubi, J. E., & Ballstreri, W. F. (1993) · Hepatology · doi:10.1002/hep.1840180513 · Cited by 88 · see citing works
Clayton, P. T., Mills, K. A., Johnson, A. W., Barabino, A. V., & Marazzi, M. G. (1996) · Gut · doi:10.1136/gut.38.4.623 · Cited by 75 · see citing works
Gonzales, E., Cresteil, D., Baussan, C., Dabadie, A., Gerhardt, M.-F., & Jacquemin, E. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2003.12.024 · Cited by 68 · see citing works
Charbonneau, A., & The, V. L. (2001) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00278-5 · Cited by 53 · see citing works
Kimura, A., Mahara, R., Inoue, T., Nomura, Y., Murai, T., Kurosawa, T., Tohma, M., Noguchi, K., Hoshiyama, A., Fujisawa, T., et al. (1999) · Pediatric Research · doi:10.1203/00006450-199904010-00022 · Cited by 51 · see citing works
Self-citationAbnormal Bile Acid Metabolism and Neonatal Hemochromatosis: A Subset with Poor Prognosis
Siafakas, C. G., Jonas, M. M., & Pérez‐Atayde, A. R. (1997) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-199709000-00015 · Cited by 51 · see citing works
Neonatal hemochromatosis: Fetal liver disease leading to liver failure in the fetus and newborn
Whitington, P. F., Kelly, S., & Ekong, U. D. (2005) · Pediatric Transplantation · doi:10.1111/j.1399-3046.2005.00357.x · Cited by 47 · see citing works
Gene analysis in δ-3-oxosteroid 5β–reductase deficiency
Sumazaki, R., Nakamura, N., Shoda, J., Kurosawa, T., & Tohma, M. (1997) · The Lancet · doi:10.1016/s0140-6736(05)62828-0 · Cited by 37 · see citing works
Self-citationTohma, M., Mahara, R., Takeshita, H., & Kurosawa, T. (1986) · Steroids · doi:10.1016/0039-128x(86)90019-x · Cited by 37 · see citing works
Self-citationImproved synthesis of 3-keto, 4-ene-3-keto, and 4,6-diene-3-keto bile acids
Leppik, R. A. (1983) · Steroids · doi:10.1016/0039-128x(83)90087-9 · Cited by 35 · see citing works
Δ4-3-Oxosteroid 5β-reductase deficiency and neonatal hemochromatosis
Clayton, P. T. (1994) · The Journal of Pediatrics · doi:10.1016/s0022-3476(06)80203-9 · Cited by 33 · see citing works
Developmental pattern of 3-oxo-Δ4 bile acids in neonatal bile acid metabolism
Inoue, T., Kimura, A., Aoki, K., Tohma, M., & Kato, H. (1997) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/fn.77.1.f52 · Cited by 25 · see citing works
Self-citationPotential Bile Acid Metabolites. XXI. A New Synthesis of Allochenodeoxycholic and Allocholic Acids.
Iida, T., Nishida, S., Chang, F. C., Toshifumi, N. I. W. A., Goto, J., & NAMBARA, T. (1993) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.41.763 · Cited by 24 · see citing works
Δ^4-3-Oxosteroid 5β -reductase deficiency and neonatal hemochromatosis (letter)
Claytone, P. (1994) · Jornal de Pediatria · Cited by 20 · see citing works
Kimura, A., Suzuki, M., Murai, T., Kurosawa, T., Tohma, M., Sata, M., Inoue, T., Hoshiyama, A., Nakashima, E., Yamashita, Y., et al. (1998) · Journal of Hepatology · doi:10.1016/0168-8278(88)80014-x · Cited by 19 · see citing works
Self-citationKimura, A., Suzuki, M., Tohma, M., Inoue, T., Endo, F., Kagimoto, S., Matsui, A., Kawai, M., Hayashi, M., Iizuka, T., et al. (1998) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-199811000-00022 · Cited by 3 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism
Rižner, T. L., & Penning, T. M. (2014) · Steroids · doi:10.1016/j.steroids.2013.10.012 · Cited by 217 · see citing works
Structural and functional biology of aldo-keto reductase steroid transforming enzymes
Penning, T. M., Wangtrakuldee, P., & Auchus, R. J. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00089 · Cited by 164 · see citing works
Feldman, A. G., & Whitington, P. F. (2013) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2013.10.004 · Cited by 143 · see citing works
Heubi, J. E., Bove, K. E., & Setchell, K. D. R. (2017) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000001657 · Cited by 65 · see citing works
5β-Reduced steroids and human Δ4-3-ketosteroid 5β-reductase (AKR1D1)
Chen, M., & Penning, T. M. (2014) · Steroids · doi:10.1016/j.steroids.2014.01.013 · Cited by 55 · see citing works
Drury, J. E., Mindnich, R., & Penning, T. M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.127779 · Cited by 51 · see citing works
Goh, V. L., Helbling, D. C., Biank, V., Jarzembowski, J. A., & Dimmock, D. (2011) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e318227e53c · Cited by 45 · see citing works
Bile Acid Synthesis Disorders in Arabs
Al‐Hussaini, A. A., Setchell, K. D. R., Alsaleem, B., Heubi, J. E., Lone, K., Spraul, A., & Jacquemin, E. (2017) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000001734 · Cited by 34 · see citing works
Lu, F., Wu, J., Hsu, H., Ni, Y., Chang, M., Chao, C., & Chen, H. (2014) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000000538 · Cited by 29 · see citing works
Self-citationSeki, Y., Mizuochi, T., Kimura, A., Takahashi, T., Ohtake, A., Hayashi, S., Morimura, T., Ohno, Y., Hoshina, T., Ihara, K., et al. (2013) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-012-9526-6 · Cited by 26 · see citing works
Self-citationJin, Y., Chen, M., & Penning, T. M. (2014) · Biochemical Journal · doi:10.1042/bj20140220 · Cited by 25 · see citing works
Chen, J.-Y., Wu, J., Kimura, A., Nittono, H., Liou, B., Lee, C., Chen, H., Chiu, Y., Ni, Y., Peng, S. S., et al. (2019) · Pediatrics & Neonatology · doi:10.1016/j.pedneo.2019.06.009 · Cited by 24 · see citing works
Self-citationNikolaou, N., Hodson, L., & Tomlinson, J. (2021) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2021.105808 · Cited by 24 · see citing works
Detlefsen, A. J., Paulukinas, R. D., & Penning, T. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031873 · Cited by 23 · see citing works
Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes
Zhang, M., Setchell, K. D. R., Zhao, J., Gong, J., Lu, Y., & Wang, J. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i7.859 · Cited by 21 · see citing works
Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment
Kimura, A., Mizuochi, T., Takei, H., Ohtake, A., Mori, J., Shinoda, K., Hashimoto, T., Kasahara, M., Togawa, T., Murai, T., et al. (2021) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06722-4 · Cited by 19 · see citing works
Self-citationWang, H. H., Wen, F., Dai, D., Wang, J., Zhao, J., Setchell, K. D. R., Shi, L.-N., Zhou, S., Liu, S., & Yang, Q. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i35.4086 · Cited by 18 · see citing works
Nittono, H., Takei, H., Unno, A., Kimura, A., Shimizu, T., Kurosawa, T., Tohma, S., & Une, M. (2009) · Pediatrics International · doi:10.1111/j.1442-200x.2008.02799.x · Cited by 17 · see citing works
Self-citationThe effect of disease associated point mutations on 5β-reductase (AKR1D1) enzyme function
Mindnich, R., Drury, J. E., & Penning, T. M. (2011) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2010.12.020 · Cited by 16 · see citing works
Neonatal liver failure owing to gestational alloimmune liver disease without iron overload
Tsunoda, T., Inui, A., Oikawa‐Kawamoto, M., Sogo, T., Komatsu, H., Kasahara, M., Nakazawa, A., & Fujisawa, T. (2014) · Hepatology Research · doi:10.1111/hepr.12381 · Cited by 16 · see citing works
5β-Dihydrosteroids: Formation and Properties
Penning, T. M., & Covey, D. F. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168857 · Cited by 15 · see citing works
Inborn errors of bile acid metabolism in Japan
Mizuochi, T., Takei, H., Nittono, H., & Kimura, A. (2023) · Pediatrics International · doi:10.1111/ped.15490 · Cited by 12 · see citing works
Self-citationChen, M., Jin, Y., & Penning, T. M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00816 · Cited by 12 · see citing works
Hirata, Y., Sakuma, Y., Ogiso, H., Nagai, R., & Aizawa, K. (2024) · Biomedicines · doi:10.3390/biomedicines13010078 · Cited by 9 · see citing works
Neonatal liver failure: a genetic and metabolic perspective
Saenz, M. S., Hove, J. V., & Scharer, G. H. (2010) · Current Opinion in Pediatrics · doi:10.1097/mop.0b013e328336ebe1 · Cited by 9 · see citing works
Urinary steroid profiling: a powerful method for the diagnosis of abnormal steroidogenesis
Koyama, Y., Homma, K., & Hasegawa, T. (2014) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.2014.904199 · Cited by 9 · see citing works
Pham, A. N., Thi, K. B., Thi, M.-H. N., Ngo, D.-N., Naritaka, N., Nittono, H., Hayashi, H., Dao, T. T., Nguyen, K. T., Nguyen, H., et al. (2022) · Medicine · doi:10.1097/md.0000000000029476 · Cited by 7 · see citing works
Self-citationHealthy Patients With AKR1D1 Mutation Not Requiring Primary Bile Acid Therapy: A Case Series
Kimura, A., Mori, J., Pham, A. N., Thi, K. B., Takei, H., Murai, T., Hayashi, H., & Nittono, H. (2023) · JPGN Reports · doi:10.1097/pg9.0000000000000372 · Cited by 6 · see citing works
Self-citationYanagi, T., Mizuochi, T., Homma, K., Ueki, I., Seki, Y., Hasegawa, T., Takei, H., Nittono, H., Kurosawa, T., Matsuishi, T., et al. (2014) · Clinical Endocrinology · doi:10.1111/cen.12596 · Cited by 6 · see citing works
Self-citationCholestasis associated to inborn errors in bile acid synthesis
Espinosa-Escudero, R. A., Herráez, E., Sánchez-Martín, A., Sanchon-Sanchez, P., Marı́n, J. J. G., & Monte, M. J. (2022) · Exploration of Digestive Diseases · doi:10.37349/edd.2022.00010 · Cited by 5 · see citing works
Recurrent AKR1D1 c.580-13T>A Variant
Zhao, J., Qiu, Y., Wang, L., Li, Z., Xie, X., Lu, Y., Setchell, K. D. R., Cheng, Y., Xing, Q.-H., & Wang, J. (2023) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2023.01.004 · Cited by 4 · see citing works
The Aldo-Keto Reductase Superfamily
Penning, T. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64092-8 · Cited by 4 · see citing works
Steroid 5β-reductase (AKR1D1): Purification and characterization
Penning, T. M. (2023) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2023.04.012 · Cited by 2 · see citing works
Cheng, Y., Li, G., Deng, M., & Song, Y. (2017) · PubMed Central · doi:10.7499/j.issn.1008-8830.2017.07.002 · Cited by 2 · see citing works
Setchell, K. D. R., Zhao, X., Reed, S., & Zhang, W. (2026) · Metabolites · doi:10.3390/metabo16070436 · Cited by 1 · see citing works
Neonatal Hemochromatosis and Gestational Alloimmune Liver Disease
Whitington, P. F. (2013) · Springer eBooks · doi:10.1007/978-1-4614-9005-0_10 · Cited by 1 · see citing works
Bile Acids and Cholestatic Liver Disease 3: Inborn Errors of Bile Acid Synthesis
Nittono, H., Kimura, A., Takei, H., Kurosawa, T., & Iida, T. (2017) · Springer eBooks · doi:10.1007/978-4-431-56062-3_9
Self-citationThe Aldo-Keto Reductase Superfamily
Penning, T. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00010-3
Human peroxisomal disorders—laboratory diagnosis
Dasouki, M. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-41379-7.00019-6
- Authors
- Ueki, I., Kimura, A., Chen, H., Yorifuji, T., Mori, J., Itoh, S., Maruyama, K., Ishige, T., Takei, H., Nittono, H., Kurosawa, T., Kage, M., & Matsuishi, T.
- Affiliations
- Kurume University (JP)
- National Taiwan University Hospital (TW)
- Kyoto University (JP)
- Kyoto Prefectural University (JP)
- Kagawa University (JP)
- Gunma Children's Medical Center (JP)
- Gunma University (JP)
- Health Sciences University of Hokkaido (JP)
- Corresponding author
- Kimura, Akihiko
- ORCID
- Venue
- Journal of Gastroenterology and Hepatology
- Publisher
- Wiley
- Published
- 2009-05
- Volume
- 24
- Issue
- 5
- Pages
- 776-785
- ISSN
- 0815-9319 (ISSN-L)
- 1440-1746
- OpenAlex
- W2146829104
- Cited by
- 41
- References
- 21
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 2 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 6 · 2013: 3 · 2012: 1
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- neonatal cholestasis, neonatal liver failure, neonatal hemochromatosis, bile acid analysis, genetic diagnosis, heterozygous mutation, compound heterozygosity
- MeSH terms
- Autopsy, Bile Acids and Salts, Cholestasis, Diagnosis, Differential, DNA Mutational Analysis, Female, Genetic Testing, Heterozygote, Humans, Infant, Newborn, Japan, Liver, Male, Metabolism, Inborn Errors, Mutation, Oxidoreductases, Phenotype, Predictive Value of Tests, Taiwan, Treatment Outcome, Fatal Outcome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review