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

doi:10.1016/j.ymgme.2021.01.004

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

Mol Genet Metab. 2021 Feb;132(2):139-145. doi: 10.1016/j.ymgme.2021.01.004. Epub 2021 Jan 12.

Authors

João Leandro¹, Aaron Bender², Tetyana Dodatko¹, Carmen Argmann¹, Chunli Yu³, Sander M Houten⁴

Affiliations

¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Genomics, Inc, Stamford, CT 06902, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: sander.houten@mssm.edu.

PMID: 33483254
DOI: 10.1016/j.ymgme.2021.01.004

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 Sugct^129/129 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.

Keywords: Glutaric acid; Glutaric aciduria; Inbred mouse strains; Lysine; Mouse genetics.

MeSH terms

Acyltransferases / genetics*
Amino Acid Metabolism, Inborn Errors / genetics*
Amino Acid Metabolism, Inborn Errors / metabolism
Amino Acid Metabolism, Inborn Errors / pathology
Animals
Disease Models, Animal
Glutarates / metabolism
Humans
Lysine / metabolism
Metabolic Diseases / genetics*
Metabolic Diseases / metabolism
Metabolic Diseases / pathology
Mice
Mice, Inbred Strains / genetics*
Oxidoreductases / deficiency*
Oxidoreductases / genetics
Oxidoreductases / metabolism
Phenotype
Transferases / genetics*

Substances

Glutarates
Oxidoreductases
Transferases
Acyltransferases
succinyl-CoA-tetrahydrodipicolinate N-succinyltransferase
glutaric acid
Lysine

Supplementary concepts

Glutaric Aciduria III