Empowering Rare Metabolic Disorder Research: Gcdh Knockout Mouse Model of Glutaric Acidemia

Understanding Glutaric Acidemia Type 1 (GA1)

Glutaric Acidemia Type 1 (GA1), also called Glutaric Aciduria Type 1, is a rare autosomal recessive metabolic disorder. It is caused by changes in the Gcdh gene. These changes affect how the body breaks down amino acids The Gcdh gene encodes the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), which plays a critical role in lysine, hydroxylysine, and tryptophan metabolism.  

Mutations disrupting GCDH activity leads to abnormal accumulation of organic acid metabolites such as glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), and glutarylcarnitine (C5DC) in the body. This buildup results in metabolic problems that primarily affect the nervous system and can cause neurodegenerative damage.

Global Prevalence & Impact 

The global rate of GA1 is about 1 in 100,000. In children, the rate is around 1 in 30,000 to 1 in 100,000. However, there are significant variances based on ethnicity and region. Infants and children with GA1 may initially develop normally, but face higher risks of developing acute encephalopathy triggered by infections, vaccinations, or surgeries. This often leads to irreversible striatal damage, with high mortality and disability rates.

Figure 1. Mechanism of brain injury in GA1 disease.^[2]

Pathogenesis of Glutaric Aciduria Type 1

Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme belonging to the dehydrogenase/decarboxylase enzyme family that is required for L-lysine, L-hydroxylysine, and L-tryptophan metabolism. GCDH is primarily located in the mitochondria of metabolically active tissues such as the liver, kidneys, and brain.

GCDH prevents toxic metabolite accumulation by catalyzing the oxidation of glutaryl-CoA to glutaconyl-CoA, which is then further decarboxylated to crotonyl-CoA. This process is a key step in the catabolism of lysine, hydroxylysine, and tryptophan. These are essential amino acids whose metabolic byproducts need to be removed quickly to prevent toxic buildup in the body. Furthermore, GCDH deficiency disrupts metabolic pathways, compromising energy supply and impacting highly energy-dependent tissues like the brain.

Mechanism of Brain Injury in GA1

In the absence of GCDH, glutaryl-CoA is improperly metabolized. This leads to the accumulation of harmful compounds such as GA, 3-OH-GA, and C5DC. These metabolites are highly toxic to the central nervous system, especially in the striatal region, potentially causing neuronal damage, vacuolization, and inflammatory responses.^[3-5] Clinical manifestations include macrocephaly, progressive dystonia, and motor dysfunction, with severe cases potentially being fatal.

Figure 2. Disruption of lysine and tryptophan metabolism in GA1.^[5]

Advancing Rare Disease Research with Gcdh Knockout Mice

To study GA1 and develop potential therapies, researchers rely on genetically modified mouse models that can mimic human disease pathogenesis and pathology. Studies have shown that Gcdh knockout mice (Gcdh KO mice) exhibit biochemical phenotypes highly similar to human GA1 disease. 

Gcdh KO mice demonstrate:

• Elevated GA and 3-OH-GA levels in urine and brain tissues
• Increased C5DC levels in serum, mirroring human patients
• High-protein diet sensitivity, leading to acute encephalopathy and brain vacuolization, often fatal within 4-5 days^[7]
• High-lysine diet (HLD) further exacerbates the phenotype. It leads to striatal neurodegeneration and age-related brain damage. Mice weaned with HLD have significantly increased mortality rates.
  
  

Gcdh Knockout mice that survive to adulthood often exhibit severe neuropathological changes, including neuronal loss, vacuolization, and intraventricular hemorrhage.^[8-9] Because of their close resemblance to human GA1 pathology, Gcdh KO mice are invaluable for:

• Pathogenesis studies to understand disease mechanisms
• Drug development and efficacy testing
• Preclinical gene therapy research, including AAV-mediated supplementation therapy ^[10-13]
  
  

Figure 3. Gcdh KO mice used for preclinical efficacy evaluation of AAV-mediated supplementation therapy ^[10]

Cyagen's Gcdh Knockout Mouse Model For Disease Research

Cyagen’s Gcdh knockout (KO) mouse model is engineered to accurately replicate the metabolic issues seen in human GA1. This makes it a valuable tool for studying how the disease progresses and testing treatment options. We developed the Gcdh KO mouse model (Product ID: C001594) by knocking out the Gcdh gene to enable studies of GA1 and other Gcdh-related metabolic disorders.

Key Features of the Gcdh KO Mouse Model:

• Human Disease Relevance: Mimics GA1-associated metabolic abnormalities.
• Genetic Accuracy: Disrupts Gcdh gene function to study the effects of deficiency.
• Preclinical Research Applications: Supports drug efficacy testing and biomarker discovery.
  
  

The Gcdh KO mouse model accumulates significant amounts of glutaric acid (GA) in plasma, brain, and liver tissues, exhibiting typical biochemical phenotypes of Glutaric Acidemia Type 1 (GA1) compared to wild-type mice. This model is an ideal tool for a variety of applications, including:

• GA1 pathogenesis mechanism studies
• Therapeutic drug research, development, & evaluations
• Gcdh/GCDH gene and protein function research

Figure 4. Comparison of GA levels in wild-type (WT) mice and Gcdh KO mice.

Gcdh KO Mice: Metabolic Disorder Research Applications

Investigating Pathophysiology and Biomarker Identification

By using the Gcdh knockout mouse model, researchers can analyze metabolic disruptions, identify biomarkers, and assess the long-term neurological impact of GA1.

Therapeutic Development and Drug Testing

These models facilitate preclinical studies on dietary interventions, gene therapy, and small-molecule drugs targeting the Gcdh gene pathway.

Learn more about Cyagen’s Gcdh KO mouse model >>

Why Choose Cyagen’s Mouse Models for Your Research?

• Customizable Genetic Models: Tailor-made solutions for metabolic disorder studies.
• Comprehensive Phenotypic Analysis: Supporting data collection on neurological and biochemical changes.
• Expert Consultation: Our team provides guidance on model selection and study design.

Request a consultation with Cyagen’s experts >>

Conclusion

The Gcdh knockout mouse model is an indispensable tool for studying rare metabolic disorders like GA1. Cyagen provides high-quality, genetically engineered mouse models to support research on Gcdh gene function, disease progression, and therapeutic innovation. By providing customized genetic modifications and comprehensive preclinical research services, Cyagen supports advancements in metabolic disorder treatments and precision medicine.

Explore More Metabolic Disease Models from Cyagen

Cyagen collaborates extensively with leading pharmaceutical companies, biotechnology firms, and academic research institutions worldwide to develop a comprehensive range of metabolic disease models. Our gene modeling experts have developed disease models related to metabolic conditions such as liver disease, obesity, diabetes, hyperuricemia, and atherosclerosis, accelerating research and drug discovery efforts in these fields.

Recommended Models for Metabolic and Cardiovascular Diseases

References:
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[2]Wajner, M. (2022). Glutaric Acidemia Type 1: An Inherited Neurometabolic Disorder of Intoxication. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham.
[3]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.
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[5]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.
[6]Koeller DM, Woontner M, Crnic LS, Kleinschmidt-DeMasters B, Stephens J, Hunt EL, Goodman SI. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet. 2002 Feb 15;11(4):347-57.
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[8]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.
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[10]Mateu-Bosch A, Segur-Bailach E, Muñoz-Moreno E, Barallobre MJ, Arbonés ML, Gea-Sorlí S, Tort F, Ribes A, García-Villoria J, Fillat C. Systemic delivery of AAV-GCDH ameliorates HLD-induced phenotype in a glutaric aciduria type I mouse model. Mol Ther Methods Clin Dev. 2024 Jun 4;32(3):101276.
[11]Barzi M, Johnson CG, Chen T, Rodriguiz RM, Hemmingsen M, Gonzalez TJ, Rosales A, Beasley J, Peck CK, Ma Y, Stiles AR, Wood TC, Maeso-Diaz R, Diehl AM, Young SP, Everitt JI, Wetsel WC, Lagor WR, Bissig-Choisat B, Asokan A, El-Gharbawy A, Bissig KD. Rescue of glutaric aciduria type I in mice by liver-directed therapies. Sci Transl Med. 2023 Apr 19;15(692):eadf4086.
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[13]Sauer SW, Opp S, Komatsuzaki S, Blank AE, Mittelbronn M, Burgard P, Koeller DM, Okun JG, Kölker S. Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I. Biochim Biophys Acta. 2015 May;1852(5):768-77.