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Cited by 47Metabolism and Genetic DisordersMitochondrial Function and PathologyCardiac electrophysiology and arrhythmias

ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein β-subunit

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Kao, Hsiao-Jung, Cheng, Ching-Feng, Chen, Yen-Hui, Hung, Shuen-Iu, Huang, Cheng-Chih, Millington, David, Kikuchi, Tateki, Wu, Jer-Yuarn +1 more·2006·Human Molecular Genetics
DOI 10.1093/hmg/ddl433
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Abstract

Using the metabolomics-guided screening coupled to N-ethyl-N-nitrosourea-mediated mutagenesis, we identified mice that exhibited elevated levels of long-chain acylcarnitines. Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located. Direct sequencing revealed a normal alpha-subunit, but detected a nucleotide T-to-A transversion in exon 14 (c.1210T>A) of beta-subunit (Hadhb) which resulted in a missense mutation of methionine to lysine (M404K). Western blot analysis showed a significant reduction of both the alpha- and beta-subunits, consistent with reduced enzyme activity in both the long-chain 3-hydroxyacyl-CoA dehydrogenase and the long-chain 3-ketoacyl-CoA thiolase activities. These mice had a decreased weight gain and cardiac arrhythmias which manifested from a prolonged PR interval to a complete atrio-ventricular dissociation, and died suddenly between 9 and 16 months of age. Histopathological studies showed multifocal cardiac fibrosis and hepatic steatosis. This mouse model will be useful to further investigate the mechanisms underlying arrhythmogenesis relating to lipotoxic cardiomyopathy and to investigate pathophysiology and treatment strategies for human MTP deficiency.

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  • Reduction of one subunit of the mitochondrial trifunctional protein in heterozygote knock-out mice leads to concomitant reduction of the other subunit.

    “Previous studies have shown that reduction of one or the other component in heterozygote knock-out mice leads to a concomitant reduction of the other subunit (31)(32)(33).”

    From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [33]

    The Discussion and Western blot and enzyme activity assay section report that both MTP subunits were reduced in affected mice with a mutation in the β-subunit. But the Identification of the mutated gene section identifies the affected mice as homozygous for a missense mutation, not heterozygous knockout mice; the paper therefore does not establish the claim for that genotype. (LLM, conf=0.89)

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  • Hepatic steatosis was observed both in mice carrying a hypomorphic allele of HADHB and in mice heterozygous for a null mutation of HADHA.

    “This was observed both in mice that carry a hypomorphic allele of the HADHB gene and, notably, in mice heterozygote for a null mutation of the HADHA gene (encoding the ␣-subunit) (32,33).”

    From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [33]

  • Reduced gene dosage or activity of the mitochondrial trifunctional protein complex leads to the accumulation of lipids in the liver (hepatic steatosis).

    “Surprisingly, there is evidence that reduced gene dosage or activity of this enzyme complex leads to the accumulation of lipids in the liver (hepatic steatosis) (32,33).”

    From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [33]

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Research works printed but not linked: 1

  1. Charles, R. and Roe, J.D. (2001) Mitochondrial fatty acid oxidation disorder. In Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. (eds), The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Companies, Inc., New York, pp. 2297-2326.

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Authors
Kao, H.-J., Cheng, C.-F., Chen, Y.-H., Hung, S.-I., Huang, C.-C., Millington, D., Kikuchi, T., Wu, J.-Y., & Chen, Y.-T.
Affiliations
  • Institute of Biomedical Sciences, Academia Sinica (TW)
  • Duke Medical Center (US)
  • China Medical University (TW)
Corresponding author
Chen, Yuan-Tsong
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2006-11-20
Volume
15
Issue
24
Pages
3569-3577
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddl433
OpenAlex
W2143009043
Cited by
47
References
33
Citations by year
2026: 4 · 2025: 3 · 2024: 3 · 2022: 1 · 2021: 3 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 5
FWCI
1.17
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Science Council
  • Academia Sinica
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
mitochondrial trifunctional protein, HADHB, HADHA, myocardial fibrosis, hepatic steatosis, long-chain acylcarnitines, lipotoxic cardiomyopathy, cardiac arrhythmias, atrioventricular dissociation, 3-hydroxyacyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, missense mutations, mouse model, N-ethyl-N-nitrosourea mutagenesis, homozygosity mapping
MeSH terms
Adipose Tissue, Animals, Base Sequence, Carnitine, Chromosome Mapping, Ethylnitrosourea, Fatty Liver, Female, Fibrosis, Male, Mice, Inbred C57BL, Multienzyme Complexes, Myocardium, Pregnancy, Blotting, Western, Polymerase Chain Reaction, Mutagenesis, Point Mutation, Mice, Lipid Metabolism Disorders, Tandem Mass Spectrometry, Mitochondrial Trifunctional Protein, Mitochondrial Trifunctional Protein, alpha Subunit, Mitochondrial Trifunctional Protein, beta Subunit

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