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.

Polycystin-1 (PC1), encoded by the PKD1 gene, is a large transmembrane glycoprotein that orchestrates critical cellular processes—including cell–cell and cell–matrix interactions, calcium signaling, and mechanosensation—in renal tubular epithelial cells. PC1 regulates various aspects of cellular function, including signal transduction, cytoskeletal remodeling, and cell adhesion. It forms a functional complex with Polycystin-2 (PC2), the product of the PKD2 gene, to maintain intracellular calcium homeostasis and facilitate mechanotransduction ^[1]. Disruption of PC1 signaling, due to PKD1 mutations—which account for approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases—undermines these regulatory pathways, promoting abnormal cell proliferation and cyst formation ^[2]. Clinically, ADPKD is characterized by the progressive development of multiple fluid-filled cysts, renal enlargement, hypertension, and eventual progression to end-stage kidney disease (ESKD). With a global incidence estimated at 1 in 400 to 1 in 1000 individuals, ADPKD affects nearly 500,000 people in the United States alone and frequently involves extra-renal manifestations, including the heart, liver, pancreas, spleen, and arachnoid membrane ^[3]. Notably, genotypic heterogeneity exists, with PKD1 mutations often associated with an earlier onset and more aggressive disease course ^[2-3]. Traditional systemic Pkd1 knockout models are typically embryonically lethal, precluding long-term pathogenesis studies. In contrast, inducible, kidney-specific conditional knockout models using the Cre-LoxP system recapitulate the clinical features of human ADPKD and permit the investigation of disease progression in adult mice ^[4-5]. Acute PKD (inducible) mice represent an inducible conditional Pkd1 knockout model generated by crossing Pkd1-floxed mice with kidney-specific, tamoxifen-inducible Cre mice (Cdh16-MerCreMer). Offspring were induced with tamoxifen during lactation to achieve targeted deletion of Pkd1 within renal tubular epithelial cells. Preliminary observations at three weeks post-induction reveal pronounced polycystic kidney disease phenotypes, including the emergence of renal cysts, a marked increase in kidney volume, and elevated serum blood urea nitrogen (BUN) levels. We will continue to monitor this model to assess its late-stage phenotypes and overall disease progression.

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 ALMS1 gene encodes the large, multi-domain ALMS1 protein, which localizes primarily to the centrosomes and basal bodies of primary cilia within cells. There, it plays a critical role in microtubule organization, ciliogenesis, endosome recycling (notably of the GLUT4 transporter), and cell cycle regulation ^[1]. Because primary cilia are sensory organelles found on nearly all cell types, the gene is expressed across a wide range of tissues, including the retina, cochlea, pancreatic islets, adipose tissue, renal tubules, and cardiomyocytes. Mutations in ALMS1 lead to Alström syndrome in humans, a rare autosomal recessive ciliopathy marked by progressive multisystem failure, including cone-rod dystrophy (blindness), sensorineural hearing loss, childhood obesity, extreme insulin resistance, type 2 diabetes, and dilated cardiomyopathy ^[2]. Research on mice with Alms1 deficiency has successfully recapitulated the clinical features mentioned above, confirming that the loss of this gene leads to stunted renal cilia, impaired intracellular trafficking in photoreceptors, and metabolic dysfunction that mirrors human disease progression ^[3]. Furthermore, a high-fat diet (HFD) can accelerate the metabolic pathological process in Alms1 KO mice, making them more susceptible to metabolic diseases such as hyperglycemia, hyperinsulinemia, and insulin resistance, while also inducing hepatic inflammation and fibrosis ^[4]. Alms1-del(c.3802-3812) mice are a research model constructed using gene-editing technology to introduce a c.3802_3812 del CAAAAACAGTT mutation into exon 8 of the mouse Alms1 gene. Both homozygous female and male Alms1-del(c.3802-3812) mice were infertile. This model can be utilized for research into the pathological mechanisms and the development of therapeutic interventions for Alström syndrome, as well as metabolic diseases such as obesity, diabetes, and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

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.

The MASP2 gene encodes MASP-2, a serum serine protease that serves as a key mediator in complement system activation. MASP-2 initiates the lectin pathway by forming complexes with pattern recognition molecules such as mannose-binding lectin (MBL) and ficolins. Upon pathogen recognition by MBL, MASP-2 is activated and subsequently cleaves complement components C4 and C2, leading to the generation of C3 convertase and triggering downstream complement activation. Beyond its role in the complement cascade, MASP-2 also contributes to the coagulation pathway by cleaving prothrombin to generate thrombin, thereby linking innate immunity and hemostasis ^[1]. Emerging evidence highlights the clinical significance of MASP2 gene polymorphisms, which are associated with altered susceptibility to infectious diseases and immune-related disorders. Reduced plasma levels of MASP-2 have been linked to increased vulnerability to HIV infection, while elevated MASP-2 activity may exacerbate inflammatory responses ^[2]. Given its pivotal role in immune regulation, MASP-2 has emerged as a promising therapeutic target. Inhibition of MASP-2 is currently under investigation as a potential strategy for treating a range of conditions, including IgA nephropathy (IgAN) ^[3], atypical hemolytic uremic syndrome (aHUS), and transplant-associated thrombotic microangiopathy (TA-TMA) ^[4]. The B6-hMASP2 mouse model, generated through precise gene editing technology, features the in situ replacement of part of the endogenous mouse Masp2 gene with the coding sequence (CDS) of human MASP2. Homozygous B6-hMASP2 mice are viable and fertile, providing a robust platform for studying the pathophysiology of autoimmune and infectious diseases. This model also serves as a valuable tool for the development and preclinical evaluation of MASP-2-targeted therapeutics, offering insights into both mechanistic and translational aspects of complement-mediated diseases.

The FGFR1 gene encodes fibroblast growth factor receptor 1 (FGFR1), a pivotal transmembrane receptor tyrosine kinase widely expressed across diverse cell types, including epithelial, mesenchymal, and neuronal lineages, playing fundamental roles in development, angiogenesis, cell proliferation, differentiation, and migration through activation of intracellular signaling cascades like MAPK/ERK, PI3K/AKT, and STAT ^[1]. Aberrant FGFR1 expression or mutations are associated with developmental syndromes and various cancers, driving tumor growth, metastasis, and therapeutic resistance; its expression is tightly regulated by diverse cellular signals ^[2]. A key splice isoform is FGFR1c, predominantly expressed in epithelial cells and characterized by a specific extracellular immunoglobulin-like domain III, conferring high-affinity binding to a subset of FGF ligands crucial for epithelial-mesenchymal interactions during development and adult tissue homeostasis ^[3]. Dysregulation of FGFR1c signaling is implicated in the pathogenesis of cancers such as breast, prostate, and lung carcinomas, contributing to tumor initiation, progression, angiogenesis, and potentially therapy resistance, highlighting the importance of understanding isoform-specific functions for targeted therapeutic interventions ^[3-4]. B6-hFGFR1c mice are humanized models generated by gene editing technology, in which the p.22R to partial intron 2 of the mouse Fgfr1 gene was replaced in situ with p.22R to 376E from the coding sequence of the human FGFR1 gene, p.377I to 823X from the coding sequence of the mouse Fgfr1 gene, and the 3'UTR of the mouse Fgfr1 gene. This model can be used to study the pathological mechanisms and therapeutic methods of cancers, metabolic diseases such as obesity, diabetes, and metabolic-associated steatohepatitis (MASH), as well as the screening and development of FGFR1c-targeted drugs, and preclinical efficacy and safety evaluations.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD) such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. This strain was a conditional mouse model expressing the human LPA gene, where the ‘loxP-Stop-loxP-hLPA’ sequence was inserted into the intron 1 of the ROSA26 safe harbor locus. When this model is bred with tool mice expressing Cre recombinase, sequence recombination occurs in the Cre-positive cells and tissues of the offspring mice. After the Cre-recombinase-mediated deletion of the stop element (LSL), specific expression of the human LPA gene can be achieved. The B6-hLPA(CKI) mice can be used for research related to atherosclerosis, and thrombotic cardiovascular diseases, as well as the development, screening, and preclinical evaluation of human LPA gene-targeted drugs.