Reference : Mild inborn errors of metabolism in commonly used inbred mouse strains.
Scientific journals : Article
Life sciences : Genetics & genetic processes
Mild inborn errors of metabolism in commonly used inbred mouse strains.
Leandro, Joao [> >]
Violante, Sara [> >]
Argmann, Carmen A. [> >]
Hagen, Jacob [> >]
Dodatko, Tetyana [> >]
Bender, Aaron [> >]
Zhang, Wei [> >]
Williams, Evan mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Bachmann, Alexis M. [> >]
Auwerx, Johan [> >]
Yu, Chunli [> >]
Houten, Sander M. [> >]
Molecular Genetics and Metabolism
Yes (verified by ORBilu)
United States
[en] Animals ; DNA Transposable Elements/genetics ; Ketone Oxidoreductases/genetics ; Male ; Metabolism, Inborn Errors/diagnosis/genetics ; Metabolomics ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Inbred Strains/genetics ; Phenotype ; Sequence Analysis, RNA ; Inborn errors of metabolism ; Inbred mouse strains ; Mouse genetics ; Recombinant inbred mouse strains ; Splicing defects
[en] Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and alpha-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains.
Copyright (c) 2019 Elsevier Inc. All rights reserved.

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