Cited by 41Metabolism and Genetic DisordersSexual Differentiation and DisordersPediatric Hepatobiliary Diseases and Treatments

SRD5B1 gene analysis needed for the accurate diagnosis of primary 3‐oxo‐Δ4‐steroid 5β‐reductase deficiency

Ueki, Isao, Kimura, Akihiko, Chen, Huey‐Ling, Yorifuji, Tohru, Mori, Jun, Itoh, Susumu, Maruyama, Kenichi, Ishige, Takashi +5 more·2009·Journal of Gastroenterology and Hepatology

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.

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Crossref · 10.1111/j.1440-1746.2008.05669.x

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  • 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.”
  • 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].”
  • 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].”
  • 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].”

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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
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

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