[Alagille syndrome associated to JAG1 gene deletion. An unusual etiology]. / Síndrome de Alagille por deleción del gen JAG1. Una causa poco frecuente.

Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal abnormalities, and distinct facial features. Most cases are due to variants in the JAG1 gene, with only a small percentage involving a complete gene deletion. OBJECTIVE: to contribute to the phenotype delineation and interpretation of a microdeletion not previously described in the literature on chromosome 20. CLINICAL CASE: A 4-month-old female patient was diagnosed with a heart murmur. An echocardiogram revealed pulmonary artery stenosis, which, combined with a prominent forehead observed on physical examination, determined her referral to clinical genetics. Because ALGS was suspected, complementary studies were performed, revealing butterfly vertebras and a genetic panel identified a pathogenic heterozygous deletion, encompassing the entire coding sequence of the JAG1 gene. To rule out a more extensive deletion, a chromosome microarray was performed, confirming a pathogenic microdeletion on chromosome 20 of 378 kb (arr[GRCh37] 20p12.2(10414643_10792802)x1). CONCLUSIONS: A targeted sequencing panel followed by confirmation with a chromosome microarray allowed the identification and delineation of a pathogenic microdeletion not previously reported in the literature, including the complete JAG1 gene in a Chilean patient whose phenotype is consistent with ALGS.

Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool.

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Identifications of three novel alleles of Serrate in Drosophila.

The Notch signaling pathway, an evolutionarily highly conserved pathway, participates in various essential physiological processes in organisms. Activation of Notch signaling in the canonical manner requires the combination of ligand and receptor. There are two ligands of Notch in Drosophila: Delta (Dl) and Serrate (Ser). A mutation mf157 is identified for causing nicks of fly wings in genetic analysis from a mutant library (unpublished) that was established previously. Immunofluorescent staining illustrates that mf157 represses the expression of Cut and Wingless (Wg), the targets of Notch signaling. MARCM cloning analysis reveals that mf157 functions at the same level or the upstream of ligands of Notch in signaling sending cells. Sequencing demonstrates that mf157 is a novel allele of the Ser gene. Subsequently, mf553 and mf167 are also identified as new alleles of Ser from our library. Furthermore, the complementary assays and the examination of transcripts confirm the sequencing results. Besides, the repressed phenotypes of Notch signaling were reverted by transposon excision experiments of mf157. In conclusion, we identify three fresh alleles of Ser. Our works supply additional genetic resources for further study of functions of Ser and Notch signaling regulation.

Akt3 activation by R-Ras in an endothelial cell enforces quiescence and barrier stability of neighboring endothelial cells via Jagged1.

Communication between adjacent endothelial cells is important for the homeostasis of blood vessels. We show that quiescent endothelial cells use Jagged1 to instruct neighboring endothelial cells to assume a quiescent phenotype and secure the endothelial barrier. This phenotype enforcement by neighboring cells is operated by R-Ras through activation of Akt3, which results in upregulation of a Notch ligand Jagged1 and consequential upregulation of Notch target genes, such as UNC5B, and VE-cadherin accumulation in the neighboring cells. These signaling events lead to the stable interaction between neighboring endothelial cells to continue to fortify juxtacrine signaling via Jagged1-Notch. This mode of intercellular signaling provides a positive feedback regulation of endothelial cell-cell interactions and cellular quiescence required for the stabilization of the endothelium.

Sacubitril/valsartan inhibits the proliferation of vascular smooth muscle cells through notch signaling and ERK1/2 pathway.

AIMS: To explore the role and mechanism of Notch signaling and ERK1/2 pathway in the inhibitory effect of sacubitril/valsartan on the proliferation of vascular smooth muscle cells (VSMCs). MAIN METHODS: Human aortic vascular smooth muscle cells (HA-VSMCs) were cultured in vitro. The proliferating VSMCs were divided into three groups as control group, Ang II group and Ang II + sacubitril/valsartan group. Cell proliferation and migration were detected by CCK8 and scratch test respectively. The mRNA and protein expression of PCNA, MMP-9, Notch1 and Jagged-1 were detected by qRT-PCR and Western blot respectively. The p-ERK1/2 expression was detected by Western blot. KEY FINDINGS: Compared with the control group, proliferation and migration of VSMCs and the expression of PCNA, MMP-9, Notch1, Jagged-1 and p-ERK1/2 was increased in Ang II group. Sacubitril/valsartan significantly reduced the proliferation and migration. Additionally, pretreatment with sacubitril/valsartan reduced the PCNA, MMP-9, Notch1, Jagged-1 and p-ERK1/2 expression.

Jagged-mediated development and disease: Mechanistic insights and therapeutic implications for Alagille syndrome.

Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.

The preferential effect of Clemastine on F3/Contactin-1/Notch-1 compared to Jagged-1/Notch-1 justifies its remyelinating effect in an experimental model of multiple sclerosis in rats.

Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund's adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2',3'-cyclic nucleotide 3'-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.

Novel JAG1 variants leading to Alagille syndrome in two Chinese cases.

Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic expression of ALGS can lead to challenges in accurately diagnosing affected infants, potentially resulting in misdiagnoses or underdiagnoses. This study highlights novel JAG1 gene mutations in two cases of ALGS. The first case with a novel p.Pro325Leufs*87 variant was diagnosed at 2 months of age and exhibited a favorable prognosis and an unexpected manifestation of congenital hypothyroidism. Before the age of 2, the second patient was incorrectly diagnosed with liver structural abnormalities, necessitating extensive treatment. In addition, he exhibited delays in language acquisition that may have been a result of SNAP25 haploinsufficiency. The identification of ALGS remains challenging, highlighting the importance of early detection and genetic testing for effective patient management. The variant p.Pro325Leufs*87 is distinct from reported variants linked to congenital hypothyroidism in ALGS patients, thereby further confirming the clinical and genetic complexity of ALGS. This emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.

Soluble and multivalent Jag1 DNA origami nanopatterns activate Notch without pulling force.

The Notch signaling pathway has fundamental roles in embryonic development and in the nervous system. The current model of receptor activation involves initiation via a force-induced conformational change. Here, we define conditions that reveal pulling force-independent Notch activation using soluble multivalent constructs. We treat neuroepithelial stem-like cells with molecularly precise ligand nanopatterns displayed from solution using DNA origami. Notch signaling follows with clusters of Jag1, and with chimeric structures where most Jag1 proteins are replaced by other binders not targeting Notch. Our data rule out several confounding factors and suggest a model where Jag1 activates Notch upon prolonged binding without appearing to need a pulling force. These findings reveal a distinct mode of activation of Notch and lay the foundation for the development of soluble agonists.

Notch ligands are biomarkers of anti-TNF response in RA patients.

Notch and its ligands play a critical role in rheumatoid arthritis (RA) pathogenesis. Hence, studies were conducted to delineate the functional significance of the Notch pathway in RA synovial tissue (ST) cells and the influence of RA therapies on their expression. Morphological studies reveal that JAG1, DLL4, and Notch1 are highly enriched in RA ST lining and sublining CD68+CD14+ MΦs. JAG1 and DLL4 transcription is jointly upregulated in RA MΦs reprogrammed by TLR4/5 ligation and TNF, whereas Syntenin-1 exposure expands JAG1, DLL4, and Notch1 expression levels in these cells. Single-cell RNA-seq data exhibit that JAG1 and Notch3 are overexpressed on all fibroblast-like synoviocyte (FLS) subpopulations, in parallel, JAG2, DLL1, and Notch1 expression levels are modest on RA FLS and are predominately potentiated by TLR4 ligation. Intriguingly, JAG1, DLL1/4, and Notch1/3 are presented on RA endothelial cells, and their expression is mutually reconfigured by TLR4/5 ligation in the endothelium. Synovial JAG1/JAG2/DLL1 or Notch1/3 transcriptomes were unchanged in patients who received disease-modifying anti-rheumatic drugs (DMARDs) or IL-6R Ab therapy regardless of disease activity score. Uniquely, RA MΦs and endothelial cells rewired by IL-6 displayed DLL4 transcriptional upregulation, and IL-6R antibody treatment disrupted RA ST DLL4 transcription in good responders compared to non-responders or moderate responders. Nevertheless, the JAG1/JAG2/DLL1/DLL4 transcriptome was diminished in anti-TNF good responders with myeloid pathotype and was unaltered in the fibroid pathotype except for DLL4. Taken together, our findings suggest that RA myeloid Notch ligands can serve as markers for anti-TNF responsiveness and trans-activate Notch receptors expressed on RA FLS and/or endothelial cells.

Cancer-associated fibroblasts-induced remodeling of tumor immune microenvironment via Jagged1 in glioma.

Tumor immunosuppression are prominent characteristics of brain glioma. Current standard modality including surgical resection and chemoradiotherapy do not significantly improve clinical outcomes. Cancer-associated fibroblasts (CAFs) that regard as important stromal cells in tumor microenvironment have been confirmed to play crucial roles in tumor development. However, the effects of CAFs on tumor immunosuppression in glioma are not well expounded. In this study, we report that CAFs contributes to the formation of glioma immunosuppressive microenvironment. Specifically, we found that glioma-derived Jagged1 enhanced the proliferation and PD-L1 expression of CAFs in vitro. Importantly, we discovered that Notch1, c-Myc and PD-L1 expression were significantly increased in high Jagged1-expressing gliomas, moreover, we further confirmed that Notch1 and PD-L1 expression located on the CAFs in glioma tissues. We also found that glioma-derived Jagged1 promotes the increase of tumor-infiltrating macrophages, M2 macrophages and Foxp3 Treg cells, as well as no significance of M1 macrophages and CD8+ T cells, indicating potential immunosuppression. This study opens up novel therapeutic strategies reversing CAF immunosuppression for gliomas.

Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins.

Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.

Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma.

Introduction: Low-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. Methods: We conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis. Results: Our findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR. Discussion: These findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway.

PURPOSE: Cervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods. METHODS: This study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells. RESULTS: The results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells. CONCLUSION: MSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.

[JAG1 affects monocytes-macrophages to reshape the pre-metastatic niche of triple-negative breast cancer through LncRNA MALAT1 in exosomes].

OBJECTIVE: To investigate the effect of JAG1 on the activities of monocytes-macrophages in pre-metastatic niche (PMN) of triple-negative breast cancer (TNBC) and explore the possible regulatory mechanism. METHODS: JAG1 expression in human TNBC MDA-MB-231 and MDA-MB-231B cells was detected using quantitative real-time PCR (qRT-PCR).Ten female nude mice were inoculated with MDA-MB-231 cells (n=5) or MDA-MB-231B cells (n=5) in the mammary fat pad, and 6 weeks later, the tumor tissues were collected for immunohistochemistry.Human monocytes THP-1 cells were treated with rhJAG1 or conditioned media (CM) of TNBC MDA-MB-231 and MDA-MB-231B cells to assess the direct effect of JAG1 on monocytes and its effect on monocytes in the PMN using monocyte-endothelial adhesion, Transwell assay, qRT-PCR and Western blotting.Transmission electron microscopy and nanoparticle tracking analyses were used to identify the effect of JAG1 on exosome release from the TNBC cells.MiRNAs interacting with lncRNA MALAT1 were identified by bioinformatics and validated using qRT-PCR. RESULTS: Compared with MDA-MB-231 cells, the invasive strain MDA-MB-231B cells showed significantly higher JAG1 expression and greater liver metastasis potential (P<0.01).Both direct treatment with rhJAG1 and treatment with the conditioned media promoted adhesion and migration and affected differentiation of the monocytes (P<0.05).Transmission electron microscopy and nanoparticle tracking analysis showed that JAG1 strongly enhanced exosome secretion from MDAMB-231 cells (P<0.01) and increased MALAT1 content in the exosomes (P<0.0001).Five candidate miRNAs related to MALAT1 and JAG1 were identified by bioinformatics analysis, and miR-26a-5p was identified as a potential target of MALAT1 in monocytes-macrophages in TMN (P<0.0001). CONCLUSION: JAG1 can promote exocrine secretion of TNBC and increase the expression of MALAT1 to cause targeted downregulation of miR-26a-5p in monocytes-macrophages in the PMN, which in turn increases JAG1 expression in monocytes-macrophages to affect their adhesion, migration and osteoclast differentiation in the PMN.

The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma.

The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients' bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients' overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.

Annexin A2 Stabilizes Oncogenic JAG1 Intracellular Domain by Inhibiting Proteasomal Degradation in Glioblastoma Cells.

Glioblastoma (GBM) is the most lethal brain cancer, causing inevitable deaths of patients owing to frequent relapses of cancer stem cells (CSCs). The significance of the NOTCH signaling pathway in CSCs has been well recognized; however, there is no NOTCH-selective treatment applicable to patients with GBM. We recently reported that Jagged1 (JAG1), a NOTCH ligand, drives a NOTCH receptor-independent signaling pathway via JAG1 intracellular domain (JICD1) as a crucial signal that renders CSC properties. Therefore, mechanisms regulating the JICD1 signaling pathway should be elucidated to further develop a selective therapeutic regimen. Here, we identified annexin A2 (ANXA2) as an essential modulator to stabilize intrinsically disordered JICD1. The binding of ANXA2 to JICD1 prevents the proteasomal degradation of JICD1 by heat shock protein-70/90 and carboxy-terminus of Hsc70 interacting protein E3 ligase. Furthermore, JICD1-driven propagation and tumor aggressiveness were inhibited by ANXA2 knockdown. Taken together, our findings show that ANXA2 maintains the function of the NOTCH receptor-independent JICD1 signaling pathway by stabilizing JICD1, and the targeted suppression of JICD1-driven CSC properties can be achieved by blocking its interaction with ANXA2.

Generation of an Alagille syndrome (ALGS) patient-derived induced pluripotent stem cell line (TRNDi032-A) carrying a heterozygous mutation (p.Cys682Leufs*7) in the JAG1 gene.

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in either the JAG1 gene (ALGS type 1) or the NOTCH2 gene (ALGS type 2). The disease has been difficult to diagnose and treat due to its muti-system clinical presentation, variable expressivity, and prenatal onset for some of the features. The generation of this iPSC line (TRNDi032-A) carrying a heterozygous mutation, p.Cys682Leufs*7 (c.2044dup), in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.

Characterization of an induced pluripotent stem cell line NCHi011-A from a 23-year-old female with Alagille Syndrome harboring a heterozygous JAG1 pathogenic variant.

Alagille syndrome (ALGS) is a multisystem disease with high variability in clinical features. ALGS is predominantly caused by pathogenic variants in the Notch ligand JAG1. An iPSC line, NCHi011-A, was generated from a ALGS patient with complex cardiac phenotypes consisting of pulmonic valve and branch pulmonary artery stenosis. NCHi011-A is heterozygous for a single base duplication causing a frameshift in the JAG1 gene. This iPSC line demonstrates normal cellular morphology, expression of pluripotency markers, trilineage differentiation potential, and identity to the source patient. NCHi011-A provides a resource for modeling ALGS and investigating the role of Notch signaling in the disease.