Stargardt disease (STGD), a hereditary macular dystrophy, is characterized by the presence of yellowish flecks within the retinal pigment epithelium (RPE), ultimately culminating in macular atrophy. Typically manifesting in childhood and adolescence, STGD leads to progressive central vision loss and mild dyschromatopsia. Fundoscopic examination may reveal pale yellow lesions exhibiting a characteristic gold foil-like sheen, accompanied by yellow-white spots surrounding the posterior pole. In advanced stages, atrophy of the RPE, photoreceptors, and choriocapillaris is observed. This bilateral and typically synchronous condition affects both eyes with comparable incidence across sexes, estimated between 1/8,000 and 1/13,000. STGD is predominantly an autosomal recessive disorder, with mutations in the ABCA4 gene accounting for approximately 95% of cases. ABCA4 encodes a retina-specific ABC transporter protein crucial for the clearance of retinal derivatives and toxic metabolites generated during rhodopsin photobleaching. Consequently, ABCA4 mutations result in the accumulation of these cytotoxic substances, triggering apoptosis of both RPE and photoreceptor cells and ultimately driving retinal degeneration. Notably, ABCA4 mutations have been implicated in a spectrum of retinal diseases, including STGD, cone-rod dystrophy (CRD), age-related macular degeneration (AMD), and retinitis pigmentosa (RP), with the specific clinical phenotype correlating with the nature and severity of the ABCA4 mutation. This strain is an Abca4 gene knockout (KO) mouse model. Gene-editing technology was used to delete the protein-coding sequence of the Abca4 gene (the homolog of the human ABCA4 gene) in mice. Previous studies have demonstrated that Abca4 KO mice exhibit delayed dark adaptation following photobleaching and a slow progression of photoreceptor degeneration^[1]. Homozygous Abca4-KO mice are viable and fertile.

The ALPL gene encodes for the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, a membrane-bound glycoprotein. This enzyme is expressed in a variety of cellular tissues, most notably in the liver, bone, and kidney, as well as in other areas like teeth and mesenchymal stem cells ^[1]. Its primary function is to act as a hydrolase, removing phosphate groups from molecules. This is a critical function for skeletal and dental mineralization, where it hydrolyzes inorganic pyrophosphate (a mineralization inhibitor) into phosphate, which then combines with calcium to form bone ^[2]. Mutations in the ALPL gene lead to hypophosphatasia (HPP), a rare inherited metabolic disease characterized by defective bone and tooth mineralization, rickets, osteomalacia, and in severe cases, seizures and respiratory complications. The severity of HPP varies, ranging from mild forms with dental issues to life-threatening perinatal forms ^[3]. Variations in the ALPL gene may also be associated with other diseases, such as osteoporosis. Research has found a high frequency of homozygous common ALPL gene variants in adult patients with atypical femoral fractures or with biochemical/clinical signs of hypophosphatasia (HPP). This suggests that variations in the ALPL gene may be linked to an increased risk of these fractures ^[4]. Furthermore, the expression and function of the ALPL gene may be relevant to cancer immunotherapy. Studies have shown that an alkaline phosphatase isoform, known as ALPL-1, is highly expressed in osteosarcoma (OS) ^[5]. The Alpl KO mouse is a knockout (KO) model in which the exon 3~4 of the Alpl gene (homologous to the human ALPL gene) has been deleted via gene-editing technology. Preliminary validation data indicate that homozygous Alpl KO mice have a short lifespan, dying within four weeks when given a specialized diet. If they are not provided with this dietary support, no surviving homozygous individuals are obtained. This model can be used to study the pathogenic mechanisms of diseases such as hypophosphatasia (HPP), osteoporosis, and osteosarcoma (OS), and to provide a basis for developing related therapeutic strategies.

The AGXT gene, mapping to chromosome 2q37.3, encodes alanine-glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate-dependent homotetrameric enzyme predominantly expressed in hepatic peroxisomes ^[1]. AGT is central to glyoxylate metabolism, catalyzing its transamination to glycine and preventing its oxidation to oxalate ^[1]. Primary Hyperoxaluria Type 1 (PH1), a rare autosomal recessive disorder affecting approximately 1-3 per million individuals, arises from over 175 identified pathogenic mutations in AGXT. These mutations typically result in deficient or mislocalized AGT, leading to marked overproduction of oxalate ^[2]. The ensuing hyperoxaluria causes deposition of calcium oxalate in the kidneys, manifesting as nephrolithiasis and nephrocalcinosis, which can progress to end-stage renal disease ^[3]. In severe cases, systemic oxalosis can occur ^[4]. Agxt-deficient mice serve as critical preclinical models, faithfully mirroring the biochemical and pathological features of PH1 and enabling the evaluation of diverse therapeutic modalities, including enzyme replacement, substrate reduction, and gene therapy. The Agxt KO mouse is a gene knockout model created using gene-editing techniques to knock out the coding sequence of the Agxt gene (the homolog of the human AGXT gene) in mice. This model is used to research the pathogenic mechanisms of primary hyperoxaluria and develop related therapeutic strategies.

The ATP7B gene encodes a copper-transporting ATPase β-peptide that is a member of the P-type cation-transporting ATPase family, which uses the energy stored in adenosine triphosphate (ATP) molecules to transport metals into and out of cells. The ATP7B protein consists of multiple transmembrane structural domains, an ATPase consensus sequence, a hinge structural domain, and a phosphorylation site, as well as at least two putative copper-binding sites ^[1]. This protein is found mainly in the liver and to a lesser extent in the kidney and brain, and functions as a copper-transporting ATPase that plays a role in transporting copper from the liver to other parts of the body. Copper is an important component of certain enzymes that maintain normal cellular function, and the ATP7B protein is important for the removal of excess copper from the body. Mutations in this gene are associated with Wilson disease (WD), which is characterized by the accumulation of copper to toxic levels that damage tissues and organs such as the liver and brain as the removal of excess copper from the body is compromised with the absence of the functional ATP7B protein ^[2-4]. This strain is an Atp7b deletion mouse model, which uses gene editing technology to knock out Atp7b, the homolog of the human ATP7B gene in mice that lack the expression of ATP7B protein and can be used in the study of disorders related to copper metabolisms such as Wilson's disease, acute liver failure, and steatohepatitis. The heterozygous Atp7b KO mice are viable and fertile, and homozygous mice have a reduced life expectancy.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the progressive loss of anterior horn motor neurons in the spinal cord, leading to muscle weakness and atrophy. This can affect the muscles that control breathing, crawling, walking, head and neck control, and swallowing, increasing the risk of pneumonia and respiratory infections in patients. SMA is the most common fatal neurogenetic disease in infancy, with an incidence rate of 1/6,000 to 1/10,000. SMA is caused by mutations in the SMN1 gene, which encodes a protein essential for motor neuron survival. The human genome also contains the SMN2 gene, which is highly homologous to SMN1 but differs in splicing patterns. A c.840C>T mutation in the splicing enhancer of exon 7 of SMN2 causes it to produce mostly truncated mRNA, which encodes a non-functional protein. Only a small portion of SMN2 mRNA, approximately 10%~15%, is spliced into full-length mRNA, which encodes functional protein ^[1]. Approximately 95% of SMA patients carry either the homozygous SMN1 exon 7 deletion mutation or the homozygous mutation that converts SMN1 to SMN2, and the inability of SMN2 expression to compensate for the deletion of SMN proteins leads to disease ^[2]. Mice are the most common preclinical experimental subjects for SMA, but they only have the Smn1 gene, and the deletion of both Smn1 alleles leads to lethality. Therefore, it is crucial to develop mouse models that can simulate human SMA pathogenesis and progression. Current therapies for SMA aim to supplement SMN1 genes or selectively regulate SMN2 splicing. Targeted therapy for SMN2 changes its splicing pattern to increase the expression of full-length SMN protein ^[3]. The application of fully humanized animal models can help promote the further translation of potential SMA-related therapies into clinical trials. This strain is a humanized SMN2 gene model of spinal muscular atrophy (SMA). The endogenous Smn1 gene in mice was replaced with the human SMN2 gene fragment to simulate the pathogenesis of SMA patients in mice. However, since the SMN2 gene mainly produces the SMNΔ7 protein, which lacks exon 7, the humanized SMN2 gene cannot fully compensate for the abnormalities caused by the loss of the Smn1 gene, resulting in an SMA-like phenotype in the model. Due to the correlation between SMA subtypes and SMN2 copy numbers, this model can be mated with Rosa26-hSMN2 mice, which have SMN2 genes inserted in chromosome 6, to increase the copy number of SMN2 in mice and improve the survival period of the model. This can simulate different SMA subtypes, which can be used for more relevant pathogenic mechanisms and preclinical studies of drugs.

Frontotemporal Dementia (FTD) is the second most prevalent form of early-onset dementia, following Alzheimer’s disease (AD). This condition is distinguished by the selective degeneration of the frontal and temporal lobes, resulting in personality and behavioral changes, language impairments, and executive dysfunction. Approximately 40%-50% of FTD cases have a familial component, with known causative genes including MAPT, FUS, and TARDBP. Of these, MAPT is the earliest discovered and most frequently implicated in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[1]. The tau protein, a microtubule-associated protein encoded by MAPT, is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, the tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons ^[2]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation ^[3-4]. Therapies targeting the MAPT gene primarily consist of small-molecule drugs and monoclonal antibodies, with indications including AD and FTD. Transgenic mice are frequently used in the drug development process, and the utilization of humanized animal models can facilitate the translation of promising treatments into clinical trials ^[5-9]. This strain is a humanized mouse model in which the endogenous mouse Mapt gene has been replaced with its human counterpart, including the 3’UTR region. This model can be utilized to study various neurodegenerative diseases, such as FTD and AD. This model is commonly named htau. 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 for specific mutations to meet the experimental needs in pharmacology and other fields.