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.

Gcdh is located on chromosome 8 of mice. Nuclease Technology was used to design sgRNA; Gcdh knockout mice were obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Gcdh is located on chromosome 8 of mice. SgRNA and ssDNA will be designed using Nuclease Technology; Gcdh conditional knockout mice will be obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm will be collected for cryopreservation.