Format

Send to

Choose Destination
Mol Genet Metab. 2019 Apr;126(4):388-396. doi: 10.1016/j.ymgme.2019.01.021. Epub 2019 Jan 24.

Mild inborn errors of metabolism in commonly used inbred mouse strains.

Author information

1
Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA.
2
Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA; Mount Sinai Genomics, Inc, One Gustave L Levy Place #1497, New York, NY 10029, USA.
3
Mount Sinai Genomics, Inc, One Gustave L Levy Place #1497, New York, NY 10029, USA.
4
Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich CH-8093, Switzerland.
5
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
6
Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA. Electronic address: sander.houten@mssm.edu.

Abstract

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-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 α-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.

KEYWORDS:

Inborn errors of metabolism; Inbred mouse strains; Mouse genetics; Recombinant inbred mouse strains; Splicing defects

PMID:
30709776
PMCID:
PMC6535113
[Available on 2020-04-01]
DOI:
10.1016/j.ymgme.2019.01.021
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center