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Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains

View ORCID ProfileJoão Leandro, Aaron Bender, Tetyana Dodatko, Carmen Argmann, Chunli Yu, View ORCID ProfileSander M. Houten
doi: https://doi.org/10.1101/2020.11.11.378463
João Leandro
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Aaron Bender
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Tetyana Dodatko
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Carmen Argmann
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Chunli Yu
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Mount Sinai Genomics, Inc, Stamford, CT 06902, USA
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Sander M. Houten
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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  • ORCID record for Sander M. Houten
  • For correspondence: sander.houten@mssm.edu
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Abstract

The glutaric acidurias are a group of inborn errors of metabolism with different etiologies. Glutaric aciduria type 3 (GA3) is a biochemical phenotype with uncertain clinical relevance caused by a deficiency of succinyl-CoA:glutarate-CoA transferase (SUGCT). SUGCT catalyzes the succinyl-CoA-dependent conversion of glutaric acid into glutaryl-CoA preventing urinary loss of the organic acid. Here, we describe the presence of a GA3 trait in mice of 129 substrains due to SUGCT deficiency, which was identified by screening of urine organic acid profiles obtained from different inbred mouse strains including 129S2/SvPasCrl. Molecular and biochemical analyses in an F2 population of the parental C57BL/6J and 129S2/SvPasCrl strains (B6129F2) confirmed that the GA3 trait occurred in Sugct129/129 animals. We evaluated the impact of SUGCT deficiency on metabolite accumulation in the glutaric aciduria type 1 (GA1) mouse model. We found that GA1 mice with SUGCT deficiency have decreased excretion of urine 3-hydroxyglutaric acid and decreased levels glutarylcarnitine in urine, plasma and kidney. Our work demonstrates that SUGCT contributes to the production of glutaryl-CoA under conditions of low and pathologically high glutaric acid levels. Our work also highlights the notion that unexpected biochemical phenotypes can occur in widely used inbred animal lines.

Take home message Glutaric aciduria type 3 is a naturally occurring trait in mice of the 129 substrains

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 11, 2020.
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Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains
João Leandro, Aaron Bender, Tetyana Dodatko, Carmen Argmann, Chunli Yu, Sander M. Houten
bioRxiv 2020.11.11.378463; doi: https://doi.org/10.1101/2020.11.11.378463
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Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains
João Leandro, Aaron Bender, Tetyana Dodatko, Carmen Argmann, Chunli Yu, Sander M. Houten
bioRxiv 2020.11.11.378463; doi: https://doi.org/10.1101/2020.11.11.378463

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