Gcdh KO Mice

Catalog Number: C001594

Strain Name: C57BL/6JCya-Gcdhem1/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Glutaric aciduria type I (GA1) is an autosomal recessive metabolic disorder caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH) [1]. GCDH, a mitochondrial enzyme belonging to the dehydrogenase/decarboxylase family, is primarily expressed in metabolically active tissues such as the liver, kidneys, and brain. It catalyzes the oxidation of glutaryl-CoA (GA-CoA) to glutaminyl-CoAglutaminyl-CoA and further decarboxylation to crotonyl-CoA, a critical step in the catabolism of lysine, hydroxylysine, and tryptophan. GCDH deficiency impairs the clearance of metabolic intermediates, leading to the accumulation of toxic substances, including glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), and glutarylcarnitine (C5DC). These metabolites are highly toxic to the central nervous system, particularly the striatum, causing neuronal damage, vacuolization, and inflammation [2-4]. Clinically, GA1 manifests as macrocephaly, progressive dystonia, and movement disorders, with severe cases being potentially fatal. Studies have shown that Gcdh knockout (KO) mice exhibit biochemical characteristics closely resembling human GA1. Levels of GA and 3-OH-GA are significantly elevated in their urine and brain tissues, and serum C5DC levels are markedly increased, consistent with the profiles observed in patients [5]. Additionally, under high-protein or high-lysine diet (HLD) conditions, Gcdh KO mice demonstrate exacerbated pathological phenotypes, including metabolite accumulation, striatal neurodegeneration, and age-related brain damage [6-7].

This strain was developed by gene editing to knock out the mouse Gcdh gene (the homolog of human GCDH), resulting in significantly elevated GA levels in plasma, brain, and liver tissues. It recapitulates the typical biochemical features of GA1 and is an ideal model for studying GA1 pathogenesis, drug development, and GCDH function.

 

Strain Strategy


Figure 1. Gene editing strategy of Gcdh KO mice. The Gcdh gene was disrupted by targeting exons 6–7 using genome-editing technologies.

 

Strain Application

  • Functional studies of GCDH protein.
  • Investigation of GA1 pathogenesis.
  • Development, screening, and preclinical evaluation of therapeutic drugs for GA1

 

Validation Data

1. Detection of Glutaric Acid (GA) Levels


Figure 2. Comparison of GA levels in wild-type (WT) and Gcdh KO mice. Data show significantly elevated GA levels in the plasma, brain, and liver tissues of Gcdh KO mice compared to WT mice, demonstrating the typical biochemical phenotype of GA1.

 

References
[1]Li Q, Yang C, Feng L, Zhao Y, Su Y, Liu H, Men H, Huang Y, Körner H, Wang X. Glutaric Acidemia, Pathogenesis and Nutritional Therapy. Front Nutr. 2021 Dec 15;8:704984.
[2]Schuurmans IME, Dimitrov B, Schröter J, Ribes A, de la Fuente RP, Zamora B, van Karnebeek CDM, Kölker S, Garanto A. Exploring genotype-phenotype correlations in glutaric aciduria type 1. J Inherit Metab Dis. 2023 May;46(3):371-390.
[3]Boy N, Mühlhausen C, Maier EM, Ballhausen D, Baumgartner MR, Beblo S, Burgard P, Chapman KA, Dobbelaere D, Heringer-Seifert J, Fleissner S, Grohmann-Held K, Hahn G, Harting I, Hoffmann GF, Jochum F, Karall D, Konstantopoulous V, Krawinkel MB, Lindner M, Märtner EMC, Nuoffer JM, Okun JG, Plecko B, Posset R, Sahm K, Scholl-Bürgi S, Thimm E, Walter M, Williams M, Vom Dahl S, Ziagaki A, Zschocke J, Kölker S. Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision. J Inherit Metab Dis. 2023 May;46(3):482-519.
[4]Li Q, Yang C, Feng L, Zhao Y, Su Y, Liu H, Men H, Huang Y, Körner H, Wang X. Glutaric Acidemia, Pathogenesis and Nutritional Therapy. Front Nutr. 2021 Dec 15;8:704984.
[5]Keyser B, Glatzel M, Stellmer F, Kortmann B, Lukacs Z, Kölker S, Sauer SW, Muschol N, Herdering W, Thiem J, Goodman SI, Koeller DM, Ullrich K, Braulke T, Mühlhausen C. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta. 2008 Jun;1782(6):385-90.
[6]Zinnanti WJ, Lazovic J, Wolpert EB, Antonetti DA, Smith MB, Connor JR, Woontner M, Goodman SI, Cheng KC. A diet-induced mouse model for glutaric aciduria type I. Brain. 2006 Apr;129(Pt 4):899-910.
[7]Seminotti B, Amaral AU, da Rosa MS, Fernandes CG, Leipnitz G, Olivera-Bravo S, Barbeito L, Ribeiro CA, de Souza DO, Woontner M, Goodman SI, Koeller DM, Wajner M. Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation. Mol Genet Metab. 2013 Jan;108(1):30-9.