B6-hATP7B*H1069Q Mouse

Hepatolenticular degeneration (HLD), also known as Wilson disease (WD), is an autosomal recessive copper transport disorder that can lead to liver failure. The incidence rate is about 1:30,000 ^[1]. The clinical manifestations of HLD mainly include chronic liver damage, and neurological and psychiatric symptoms, and can occasionally cause acute liver failure and hemolytic anemia. Its typical manifestation is the combination of liver disease and movement disorders in adolescence or early adulthood, but there is a large variation in phenotypic differences among patients, and up to 60% of patients have neurological or psychiatric symptoms ^[2]. Studies have shown that mutations in the ATP7B gene are associated with HLD. The characteristic feature is that with the loss of functional ATP7B protein, the clearance of excess copper is affected, leading to copper accumulation to toxic levels, damaging tissues and organs such as the liver and brain ^{[1, 3-4]}. The copper ion transport ATPase β-peptide encoded by the ATP7B gene is a member of the P-type cation transport ATPase family. This family uses the energy stored in ATP to transport metals into and out of cells. The ATP7B protein consists of multiple transmembrane domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites ^[5]. This protein mainly exists in the liver, with small amounts found in the kidneys and brain. Its function as a copper transport ATPase plays a role in transporting copper from the liver to other parts of the body. More than 900 pathogenic mutations of the ATP7B gene have been reported, with the mutation types mainly concentrated in missense, nonsense, or frameshift mutations, and other mechanisms include exon skipping, large deletions, and intron variations. The most common mutation in patients from Northern and Eastern Europe is H1069Q, but its frequency varies greatly among countries ^[2].

Hepatolenticular degeneration (HLD) treatments are mainly categorized into pharmacotherapy and surgical intervention. Pharmacotherapy is aimed at alleviating symptoms, preventing disease progression, and preventing complications, while surgery is typically liver transplantation. With the continuous exploration of the genetic etiology of Wilson’s disease, targeted gene therapy is expected to become the next "star therapy." Currently, multiple biotechnology companies and research institutions, including Prime Medicine and LogicBio Therapeutics, are developing a variety of gene editing therapies based on CRISPR/Cas9, Prime Editor, or other technologies to correct mutations in the ATP7B gene or replace the mutated ATP7B gene as a whole. These highly promising therapies are currently in preclinical studies ^[6-15]. Given that these gene editing therapies require precise targeting of the human ATP7B gene, humanizing mouse genes will help accelerate the entry of gene therapy into the clinical stage. This strain is a humanized point mutation model constructed by introducing the common pathogenic mutation p.H1069Q (CAC>CAA) into the humanized ATP7B gene of B6-hATP7B mice (Catalog No.: I001130). This model is suitable for studying the pathogenic mechanisms of Wilson's disease, and homozygous animals are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain and provide customized services to meet the experimental needs.