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Alagille syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Alagille syndrome. Core disease mechanisms, molecular and cellular pathway...

2026-04-13
Asta MONDO:0007318 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Alagille syndrome. Core disease mechanisms, molecular and cellular pathway...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Ocular Findings in Siblings With Alagille Syndrome: A Report of Two Cases

  • Authors: Ricardo A Murati Calderón, Julian A Menendez Sepulveda, N. Izquierdo
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/ab7b77221dbad9c4fc3b0f034fe9d63b00dd547a
  • DOI: 10.7759/cureus.95312
  • PMID: 41293383
  • PMCID: 12641326
  • Summary: Two Latino siblings with ALGS and glaucoma share the previously described JAG1 c.925G>C (p.Gly309Arg) variant, suggesting that disruption of the Notch pathway may increase the risk of anterior-segment (mesodermal) dysgenesis and predispose individuals with ALGS to glaucoma.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Alagille syndrome (ALGS) is a rare multisystemic disorder characterized by a wide range of clinical manifestations, including ophthalmic findings [1]. Major diagnostic criteria of patients with ALGS include cholestatic liver disease due to bile duct paucity, characteristic facial dysmorphism, cardiovascular anomalies (mainly pulmonary artery stenosis), and renal and skeletal abnormalities, such as butterfly vertebrae [2]. Ocular features in patients with the syndrome include posterior embryotoxon, iris abnormalities, optic disc anomalies, diffuse fundus hypopigmentation, and speckling of the retinal pigment epithelium [1,3]. > The primary genetic cause of ALGS is mutations in the JAG1 gene, inherited as an autosomal dominant trait [4]. The JAG1 gene encodes the jagged 1 protein, a key component of the Notch signaling pathway. Human jagged 1 is the ligand for the receptor notch 1, which is involved in signaling processes [5]. JAG1-Notch signaling regulates the differentiation of endothelial cells into mesenchymal cells, a process known as endothelial-mesenchymal transition [6]. This pathway is vital for forming bile ducts, heart valves, and other key structures, such as the neural-crest-derived anterior segment of the eye, commonly affected in ALGS [7,8]. > Perturbation of the Notch pathway in the anterior segment has been implicated in the prominence of Schwalbe's line, known as posterior embryotoxon, abnormal development of the trabecular meshwork and Schlemm's canal, and various iris anomalies [1]. These alterations provide a biologically plausible mechanism for impaired aqueous outflow and subsequent elevation of intraocular pressure (IOP). In animal models, mutations in JAG1 have been shown to similarly cause abnormalities and dysgenesis of the trabecular meshwork and iridocorneal angle, supporting this mechanistic link [9]. > Alagille syndrome affects approximately 1 in 30,000 to 70,000 live births globally and exhibits variable expressivity, complicating diagnosis and management [1].

[2] Successful long-term survival following lipiodol chemoembolization for hepatocellular carcinoma in Alagille syndrome: A case report

  • Authors: Imad Akasbi, I. Chaouche, N. Bouardi, A. Akammar, H. O. Chahdi et al.
  • Year: 2025
  • Venue: Radiology Case Reports
  • URL: https://www.semanticscholar.org/paper/6679c324bcffe0ca254e661188deda9454e73e67
  • DOI: 10.1016/j.radcr.2025.04.125
  • PMID: 40492163
  • PMCID: 12148378
  • Summary: A 29-year-old female, diagnosed with Alagille syndrome in infancy, who developed infiltrative HCC at age 20 and underwent lipiodol-based transarterial chemoembolization (TACE) in 2015, has achieved an exceptional 9-year survival post-treatment with stable imaging and no recurrence, highlighting TACE’s potential as an effective palliative treatment for HCC in Alagille syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > The development of HCC in Alagille syndrome is caused by fibrotic changes, genetic instability in hepatocytes and oncogenic mutations [1][2][3]. Furthermore, in the context of genetic predisposition, mutations in the JAG1 or NOTCH2 genes can contribute directly to carcinogenesis by perturbing cell signaling pathways [3][4][5][6]. Nonspecific markers such as bilirubin and the presence of xanthomas have been identified as potential predictors of severe liver damage with an increased risk of malignancy [ 1 ,2 ,4 ,5 ]. > The management of Alagille syndrome and its complications requires a multidisciplinary approach. Regular monitoring of liver function and imaging is essential for early detection of malignancies. Liver transplantation remains the definitive treatment for end-stage liver disease and HCC in this syndrome, offering better survival outcomes. However, challenges such as organ availability and per-operative risks need to be surmounted [3][4][5]. > HCC in Alagille syndrome remains poorly studied, with only a handful of reported cases. In a retrospective study by Pham et al., 1 patient with Alagille syndrome underwent chemoembolization with good response, though liver transplantation was ultimately required. Geramizadeh et al. described another case of pediatric HCC in Alagille syndrome, where chemoembolization was performed twice, achieving a durable clinical and radiological response [ 7-9 ] Our patient's case stands out due to the exceptional long-term survival of 9 years without liver transplantation, highlighting the potential role of repeated chemoembolization as a bridging or palliative strategy when transplant is not feasible. > Emerging therapies for Alagille syndrome target the underlying genetic and molecular mechanisms, especially the Notch signaling pathway (Kohut et al. [ 3 ]). Gene-based treatments and small molecules are being developed to address JAG1 or NOTCH2 mutations. Novel agents also aim to improve bile acid metabolism and reduce fibrosis (Ayoub et al. [ 5 ]). These approaches may help manage cholestasis and prevent liver damage.

[3] Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

  • Authors: Ana Sánchez-Monteagudo, E. Ripollés, M. Berenguer, C. Espinós
  • Year: 2021
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/e55ab21bb219d044caf3ddbc8064ed4e79fafe0d
  • DOI: 10.3390/biomedicines9091100
  • PMID: 34572285
  • PMCID: 8471362
  • Citations: 37
  • Influential citations: 1
  • Summary: The characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Alagille syndrome (ALGS; MIM 118450) is a multisystem disorder caused by mutations in JAG1 or NOTCH2 genes transmitted in an autosomal dominant way. ALGS is characterized by the scarcity of bile ducts in liver biopsy and, at least, the presence of three of five clinical features: cholestasis, congenital heart defects, ocular abnormalities, bone anomalies and characteristic facies. Renal disease, development, and growth retardation may occur less frequently. > Nearly 400 mutations have been annotated for JAG1 implicated in ALGS, while cases owing to NOTCH2 mutations are less frequent. JAG1 encodes Jagged-1 protein, a ligand of the Notch-1 family of transmembrane receptors, which are involved in signaling pathways related to cell fate determination during embryogenesis. Overall, there are no clear genotype-phenotype correlations for this syndrome and its high variable expressivity and incomplete penetrance are well recognized [135,136]. Amson et al. [137] reported two siblings who both presented with liver disease but were carriers of two different genetic alterations. The index case was diagnosed with ALGS, and molecular analysis showed that he was a carrier of a de novo duplication in JAG1 and a mutation in ATP7B. His brother was diagnosed with WD and resulted to be a compound heterozygous for ATP7B mutations. The index case had abnormal liver function, but he had no bile duct paucity on liver biopsy. So far, the question whether the ATP7B variant contributes to the clinical outcome in the index case remains unanswered.

[4] Phenotypic Divergence of JAG1‐ and NOTCH2‐Associated Alagille Syndrome & Disease‐Specific NOTCH2 Variant Classification Guidelines

  • Authors: Shannon M. Vandriel, Li-Ting Li, H. She, Jian-She Wang, K. Loomes et al.
  • Year: 2025
  • Venue: Liver International
  • URL: https://www.semanticscholar.org/paper/9afc79d27f6315be4479512b7893a3ee7c5deb70
  • DOI: 10.1111/liv.70251
  • PMID: 40742203
  • PMCID: 12312628
  • Citations: 1
  • Summary: Using a large, international patient cohort acquired through the Global ALagille Alliance (GALA) study, this work sought to improve classification of NOTCH2 variants and study phenotypic differences between NOTCH2‐ and JAG1‐related disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.443) > Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that is the most common inherited cause of neonatal cholestasis, with an overall incidence of 1:30 000 [1]. Additional clinical features include characteristic facies, cardiac, skeletal, renal, vascular and ocular involvement [2][3][4][5][6]. The molecular aetiology of ALGS stems from dysfunctional Notch signalling caused by pathogenic variants in either the Notch pathway ligand Jagged1 (JAG1) or the Notch receptor, NOTCH2, which account for 94.3% and 2.5% of cases, respectively [7]. A clinical diagnosis of ALGS relies on the presence of at least three disease features or the presence of one disease feature and either a family history in a first degree relative or a confirmed pathogenic/likely pathogenic variant identified in JAG1 or NOTCH2. JAG1-related ALGS has been well-characterised with over 700 variants described in the Human Gene Mutation Database (HGMD) [8]. The majority of JAG1 variants (including full gene deletions) result in loss-of-function (LoF) of the JAG1 protein, implicating haploinsufficiency as the underlying disease mechanism [4,9]. In ALGS, there is remarkable variability in both disease severity and organ involvement including among family members harbouring the same pathogenic variant [3,[10][11][12][13][14]. The mechanisms underlying variable expressivity remain unknown but likely involve the contribution of genetic modifiers [15][16][17][18]. Consequently, cohort-based studies have failed to establish a genotype-phenotype association among patients with ALGS [19][20][21]. > The functional consequences of variants in NOTCH2 are less well understood, with only 35 variants reported in HGMD [8]. Given the paucity of supportive functional data and the low number of individuals with a NOTCH2 variant, variant of uncertain significance (VOUS) rates for NOTCH2 are high.

[5] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[6] Generation of iPSC line NCHi012-A from a patient with Alagille syndrome and heterozygous pathogenic variant in the JAG1 gene

  • Authors: D. Cunningham, Isaac Stanberry, Shiqiao Ye, Matthew Alonzo, Ming-Tao Zhao et al.
  • Year: 2023
  • Venue: Stem cell research
  • URL: https://www.semanticscholar.org/paper/878fcbd80b2dee6304fe62f6e00c3eca45811630
  • DOI: 10.1016/j.scr.2023.103177
  • PMID: 37549562
  • PMCID: 10528323
  • Citations: 1
  • Summary: An initial characterization of NCHi012-A is reported, derived from an ALGS patient with cholestatic liver disease and mild pulmonary stenosis, who is heterozygous for a 2 bp deletion in the JAG1 coding sequence.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > Alagille syndrome (ALGS) is an autosomal dominant genetic disorder with incomplete penetrance that affects ~1 in 70,000 live births (Kohut et al., 2021). Clinical features of ALGS are variable, but primarily involve a paucity of intrahepatic bile ducts resulting in cholestasis, and may also include cardiac, skeletal, ocular and renal abnormalities. The most common cardiac defects are peripheral pulmonary stenosis (75%) and tetralogy of Fallot (7-13%) (Mitchell et al., 2018). About 95% of ALGS patients carry pathogenic variants in JAG1 that encodes Jagged1, a transmembrane ligand that binds Notch receptors to mediate inter-cellular signaling (Gilbert et al., 2019). In ALGS, JAG1 variants are present across all regions of the gene, with no clear correlation between mutation position and specific clinical features (Kohut et al., 2021). Thus, it is thought that the dominant inheritance of ALGS likely arises from JAG1 haploinsufficiency rather than dominant negative effects. > Differences in genetic modifiers between ALGS patients may account for the broad range of phenotypes they display. Differentiation of patient-derived iPSC lines into relevant cell lineages in vitro provides a powerful approach toward identifying the factors and mechanisms that contribute to the complex ALGS phenotype. > Here we describe iPSC line NCHi012-A that was derived from an ALGS patient with end-stage cholestatic liver disease requiring a liver transplant, chronic kidney disease (Stage I) with secondary hypertension and mild bilateral pulmonary stenosis. NCHi012-A is heterozygous for a 2 bp deletion [NM_000214.3(JAG1): c.1485_1486delCT] that results in a frameshift near the middle of the JAG1 coding sequence (dbSNP: rs876660981) (Raas-Rothschild et al., 2002).

[7] Advances in origin, evolution, and pathogenesis of optic disc drusen: A narrative review

  • Authors: Xiyuan Liu, Yan Yan
  • Year: 2025
  • Venue: Indian Journal of Ophthalmology
  • URL: https://www.semanticscholar.org/paper/c6c18910b365394e37939bef28b5ffd85d27d7b1
  • DOI: 10.4103/IJO.IJO_937_24
  • PMID: 40272291
  • PMCID: 12121874
  • Citations: 4
  • Influential citations: 1
  • Summary: A database search on PubMed and Google Scholar for ODD publications used the terms: (“optic disc drusen”) OR (“optic nerve head drusen”) OR (“drusen of optic nerve head”) to identify publications.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Volume 73 Issue 5 one out of 27 relatives had buried ODD, estimated at 3.7%, higher than the average prevalence estimates in the studies. > Accordingly, researchers have attempted to find candidate genes for ODD [Table 1]. In 1997, Nischal reported a strong correlation between Alagille syndrome (AS) and ODD in young children under ultrasound evidence. [13] The findings showed that the prevalence of unilateral ODD and bilateral ODD in patients with AS was 90% and 65%, respectively. ODD was the most common ophthalmologic abnormality in infants with several types of cholestasis, including AS, with an incidence of 10.7%. [14] Gilbert attributed the causal genes for AS to JAGGED1 within 20p12 and NOTCH2 within 1p12 by disrupting the Notch signaling pathway. [15] Given the critical role of Notch signaling in cellular fate determination and its activity during development and in organ systems, it is hypothesized that ODD may be independently influenced by JAGGED1 and NOTCH2 genes. ODD has recently been identified as a complex ophthalmic syndrome linked to a mutation in the membrane-type frizzled-related protein (MFRP) gene. Studies suggested that MFRP might be involved with Table 1: Lists of possible genes and syndromes associated with optic disc drusen and related clinical presentations

[8] Alagille Syndrome and Its Clinical and Laboratory Features: A Case Report

[9] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

  • Authors: K. Lourida, G. Louridas
  • Year: 2022
  • Venue: Cardiogenetics
  • URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
  • DOI: 10.3390/cardiogenetics12020015
  • Citations: 4
  • Influential citations: 1
  • Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[10] Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome

  • Authors: E. Micaglio, A. Andronache, P. Carrera, M. Monasky, E. Locati et al.
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/32a91436094e3785545efb46d990e7a5b3173304
  • DOI: 10.3390/ijms20246247
  • PMID: 31835735
  • PMCID: 6940840
  • Citations: 16
  • Summary: A novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagilles patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > It has been known since 2000 that the JAG1 gene is expressed in normal human neural tube [12]. In spite of this, clinical descriptions of neural tube defects in molecularly confirmed Alagille patients are limited. No functional data about the role of the JAG1 heterozygous mutation in neural tube defects are available to date. However, it has been demonstrated that apical/basal cell polarity is essential for neural tube closure [13]. In particular, it is very well known that JAG1 is part of the NOTCH cell pathway [14] and that NOTCH signaling has an essential impact on apical/basal cell polarity [13]. The most updated data indicate that Notch signaling plays a role in both differentiation and the organization of development in the central nervous system. > To the best of our knowledge, this is the first description of a neural tube defect as an onset sign of Alagille in a pediatric patient. The vast majority of children affected by this condition display an association between cholestasis (96%) and congenital heart malformation, while the most common kind of heart involvement is pulmonic stenosis (67% of patients [15]). Spina bifida occulta has already been described in patients clinically affected by Alagille syndrome [16]. In these cases, already published, no mention about mutation(s) nor genes involved has never been provided. Instead, here we describe for the first time ever a possible cause for this phenotype, including a case of spina bifida occulta in the apparent absence of other major environmental and genetic causes. It is remarkable that the same dose of folic acid had been taken by the mother for the first trimester of gestation in the previous pregnancy, which resulted in a healthy male newborn without any clinical signs of neural tube defect. > In the present case, the clinical picture was characterized at its onset by congenital spina bifida occulta and cyanotic heart disease: this is not a common association to lead the pediatrician to the suspicion of Alagille syndrome. This condition is more commonly suspected due to the association between cholestasis and congenital heart malformations.

[11] Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

  • Authors: G. Vitale, A. Mattiaccio, A. Conti, Laura Turco, M. Seri et al.
  • Year: 2022
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/36d42bac26fd444f619e3b6487c8a13a224b910e
  • DOI: 10.3390/cancers14143421
  • PMID: 35884482
  • PMCID: 9322180
  • Citations: 20
  • Influential citations: 1
  • Summary: The available data on FIC-related hepatobiliary cancers is reviewed, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > Historically, inherited cholestatic diseases such as PFIC and Alagille syndrome are considered neonatal and pediatric disorders, characterized by a defect in BAs transport or structure of tight junctions at the level of hepatocyte, secondarily impairing bile excretion and liver accumulation resulting in itching, hepatocyte injury and cirrhosis [14]. Eight different PFIC types have now been described, other than MYO5B, which is another gene responsible for a clinical picture similar to PFICs. > Figure 1 summarizes the proteins involved in BAs metabolism and transport, their role and their position in hepatocytes, biliocytes and intestinal cells. > The eight genes involved in these mendelian diseases are present on OMIM ® . Table 1 summarizes genes, year of discovery, and main phenotypes correlated to PFIC including association with the HBCs cases: > -ATP8B1 gene (PFIC1): it is responsible for the synthesis of a lipid flippase, able to maintain the asymmetry of the cell membrane by the translocation of phospholipids from the exoplasmic to the cytoplasmic leaflet, having a protective role against excessive concentrations of BAs [14]; -ABCB11 gene (PFIC2): coding for the bile export pump (BSEP), ABCB11 regulates the excretion of monovalent BAs from hepatocytes to bile canaliculi against a concentration gradient. The accumulation of BAs in hepatocytes is induced by a less expression or a malfunction of BSEP, resulting in cellular injury and alterations of the enterohepatic pathway of BAs [14]; -ABCB4 gene (PFIC3): alterations of the MDR3 glycoprotein, a phosphatidylcholine flippase sited in the canalicular membrane of hepatocytes, lead to the disease; MDR3 protein carries phosphatidylcholine from the hepatocytes into the bile canaliculus, protecting the cholangiocytes from the detergent activity of BAs and reducing cellular injury.

[12] Gene Therapy for Acquired and Genetic Cholestasis

  • Authors: Javier Martínez-García, Angie Molina, G. González-Aseguinolaza, N. Weber, C. Smerdou
  • Year: 2022
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/ce8b7aeadf153ca3ed48a16677ba2a92d831ab62
  • DOI: 10.3390/biomedicines10061238
  • PMID: 35740260
  • PMCID: 9220166
  • Citations: 8
  • Influential citations: 1
  • Summary: Important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.
  • Evidence snippets:
  • Snippet 1 (score: 0.356) > ALGS arises due to mutations in genes involved in the Notch signaling pathway, such as JAG1 and NOTCH2, and the majority of patients present cholestasis and a deficiency of bile ducts [21]. CTX is caused by mutations in the CYP27A1 gene, resulting in impaired BA biosynthesis The role of BSEP in the functioning of the hepatobiliary system is very important, as mutations in different genes involved in BA metabolism and transport, such as ABCB11, NR1H4, and MYO5B causing its deficiency, cause PFIC [14][15][16]. In addition, depending on the severity of the disease, inherited intrahepatic cholestasis resulting from mutations in ATP8B1 or ABCB11 can be classified as either PFIC1 or 2, respectively, or benign recurrent intrahepatic cholestasis (BRIC) 1 or 2, respectively. Sometimes it is clinically difficult to discern between PFIC and BRIC because, in both cases, patients may present mild cholestasis with long-term complications [17]. In addition, some missense mutations in less conserved regions of the ABCB11 and ABCB4 genes promote the development of more moderate variants of cholestasis such as BRIC2, ICP, cholesterol cholelithiasis, drug-induced cholestasis, adult biliary cirrhosis, transient neonatal cholestasis, and others [18,19]. In addition, mutations in cholangiocyte transporter genes (e.g., the cystic fibrosis transmembrane conductance regulator (CFTR) gene) can cause cholestasis. In fact, a direct association between cystic fibrosis and cholestatic conditions, such as bile duct complications, gallstones, and primary sclerosing cholangitis, has been observed due to mutations in CFTR [20]. Other genetic multisystemic diseases associated with cholestatic disorders include Alagille syndrome (ALGS) and cerebrotendinous xanthomatosis (CTX).

[13] Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

  • Authors: E. Andersson, Indira V. Chivukula, Simona Hankeová, Marika Sjöqvist, Y. Tsoi et al.
  • Year: 2017
  • Venue: Gastroenterology
  • URL: https://www.semanticscholar.org/paper/66b377d07a4fb3b1eae49d5eb74694afba76ab7b
  • DOI: 10.1053/j.gastro.2017.11.002
  • PMID: 29162437
  • PMCID: 7007299
  • Citations: 105
  • Influential citations: 2
  • Summary: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology.
  • Evidence snippets:
  • Snippet 1 (score: 0.354) > Background & Aims Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. Methods Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. Results Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.351) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] Research trends and hotspots of adult Alagille syndrome: a bibliometric analysis

  • Authors: Qing Liu, Jie Yang, Wentian Liu, Chao Sun
  • Year: 2025
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/49e60bed104eaacbaf2e31762fc85839fb6524c8
  • DOI: 10.1186/s13023-025-03855-5
  • PMID: 40597401
  • PMCID: 12210516
  • Citations: 1
  • Summary: This study systematically summarizes the results of adult ALGS researches, describes and predicts research hotspots and trends on a global scale, which may be helpful for clinicians and researchers to improve their clinical understanding of this disease, and provide a valuable reference for future intensive investigation.
  • Evidence snippets:
  • Snippet 1 (score: 0.351) > Research trends and hotspots of adult Alagille syndrome: a bibliometric analysis

[16] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 2
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.350) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[17] Notch1 siRNA and AMD3100 Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease

  • Authors: Chunli Zhu, Yiheng Cheng, Lei Yang, Yifu Lyu, Jingjing Li et al.
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/f3a6939b33db32d6c141825ae843fbc27c1d1ad8
  • DOI: 10.3390/biomedicines13020486
  • PMID: 40002899
  • PMCID: 11853639
  • Citations: 2
  • Summary: This work demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release.
  • Evidence snippets:
  • Snippet 1 (score: 0.348) > Metabolic dysfunction-associated steatotic liver disease (MASLD), renamed from non-alcoholic liver disease (NAFLD), is considered one of the most common causes of chronic liver diseases, including progression of hepatic steatosis, metabolic dysfunctionassociated steatohepatitis (MASH), fibrosis, and hepatocellular carcinoma (HCC) [1,2]. Meanwhile, MASLD is a multisystem disease with some extrahepatic complications like cardiovascular disease (CVD), type 2 diabetes mellitus, and chronic kidney disease [3]. MASLD represents a significant and progressively increasing global health and economic burden, while prevalence of MASLD continues to increase substantially worldwide [4]. The good news is that the FDA approved the first drug for the treatment of MASH, Rezdiffra, in 2024, but the long-term efficacy of the drug is still being studied and evaluated [5]. Moreover, other promising drugs targeting mechanisms of MASLD are still under clinical trials. Apart from developing new drugs, considering the complex pathogenesis of MASLD, it is necessary to propose more clinical protocols for drug combination to treat MASLD, as efficacy can be increased and side effects can be reduced in this way [6]. > The Notch signaling pathway is extremely evolutionarily conserved and is extensively involved in various diseases of the nervous, immune, and cardiovascular systems [7]. In MASLD progression, the Notch signaling pathway is associated with hepatic lipid accumulation, insulin resistance (IR), oxidative stress (OS), fibrogenesis, and autophagy progression in MASLD [8]. Specifically, the Notch signaling pathway is involved in the activation and effect of pro-inflammatory macrophages, and it directly regulates the transcription of pro-inflammatory signature genes, such as Il6, Il12b, and Nos2 [9]. In monocytes, the Notch signaling pathway plays a crucial role in cell migration and differentiation [10], and it also mediates the transition between the Ly6C high inflammatory phenotype and the Ly6C low circulating surveillance phenotype through mechanisms similar to those in macrophages [11].

[18] 20p chromosome inverted duplication syndrome with phenotypes of congenital heart disease, anorectal malformation and megacolon

  • Authors: Guangxian Yang, Wenwen Fan, Ni Yin, Zhiping Tan
  • Year: 2024
  • Venue: BMJ Case Reports
  • URL: https://www.semanticscholar.org/paper/161ebed1bf25e3dd2e6a43067e6bba95a6cb9bd9
  • DOI: 10.1136/bcr-2024-261019
  • PMID: 39510612
  • Summary: A middle childhood case of 20p chromosome inverted duplication deletion syndrome is reported, characterised by intellectual disability, backward movement, unique facial features, congenital heart disease: ventricular septal defect, patent foramen ovale, pulmonary hypertension and congenital anorectal malformation.
  • Evidence snippets:
  • Snippet 1 (score: 0.345) > Cholestasis is caused by a lack of intrahepatic bile ducts; renal malformations (mainly renal dysplasia) exist in approximately 39% of these patients. 11 Rodriguez et al 12 first reported the ARM phenotype of Alagille syndrome in a male at late adolescence with signs of embryonic tail dysplasia: anal atresia, rectourethral fistula, lumbosacral abnormalities and right renal dysplasia. More than 95% of patients with ALGS1 have heart defects, especially in the right-ventricular system (from mild peripheral pulmonary stenosis to severe tetralogy of fallot involving the right ventricle and pulmonary artery). The JAG1 gene is involved in the notch signalling pathway, regulation of which is essential for the formation of ventricular-outflow tracts and ventricular trabeculae in the embryonic heart. 13 Our patient's severe jaundice in the neonatal period and CHD (especially VSD) might be strongly related to the JAG1 gene. Bone morphogenetic protein 2 (BMP2; OMIM #112 261), 14 located at 20p12.3, is a gene encoding the transforming growth factor beta (TGF-β) superfamily. The TGF-β signalling pathway constitutes a large cytokine superfamily that plays an important role in regulating the growth, migration, proliferation, differentiation and apoptosis of cells in a series of processes relating to cell differentiation and growth. Variations of BMP2 are associated with the disease brachydactyly type A2 (OMIM #112 600), facial dysmorphism, short stature and skeletal anomalies with or without cardiac anomalies (SSFSC1; OMIM #617 877). This child's toe and cardiac abnormalities might also be related to this gene. > In addition, sex-determining region Y-related 3-hydroxy-3-methylglutaryl box 12 (SOX12; OMIM #609 147) and neurensin 2 (NRSN2; OMIM #610 666), which are located in the 20p subtelomere region, are associated with developmental delay, especially of language. 15

[19] Alagille Syndrome: A Case Report

  • Authors: Madhabi Baidya, Syed Shafi Ahmed, Salauddin Mahmud
  • Year: 2022
  • Venue: Dhaka Shishu (Children) Hospital Journal
  • URL: https://www.semanticscholar.org/paper/bcd83bafc2117c53a71fb2633b40bda1331325c3
  • DOI: 10.3329/dshj.v37i1.59120
  • Summary: Abstract not available DS (Child) H J 2021; 37(1): 71-73
  • Evidence snippets:
  • Snippet 1 (score: 0.344) > Alagille syndrome is an autosomal recessive disorder which occur because of notch signaling pathway defects, primarily as a result of JAG1 mutation (ALG type 1), but it conjointly occurs seldom because of neurogenic locus notch homolog protein (NOTCH2) mutation (ALG type 2). 1,2 The syndrome and severity of Alagille can vary widely, often in the same family, from person to person. Some people may have mild form, while others may have more severe form. It is characterized by abnormalities in the liver, heart, eyes, face and skeleton. The main clinical manifestation of Alagille syndrome is cholestasis resulting from paucity of intrahepatic bile ducts and it is commonly associated with other clinical signs: heart disease, skeletal abnormalities, ocular abnormalities and facial dysmorphism. 3 pical facial alterations include sunken eyes, wide forehead, prominent chin, bulbous nose and small or malformed ears. Laboratory findings are increased blood levels of bile acids and direct bilirubin; increased transaminase, alkaline phosphatase, and gamma-glutamyltransferase activities and hypercholesterolemia. Histological findings are the presence of bile pigments in the cytoplasm of hepatocytes and in the lumen of bile canaliculi, ductules and ducts often associated with secondary cell injury. 4,5 veral diseases can present cholestasis as a symptom; therefore, differential diagnosis continues to pose a challenge for pediatrician. In this case report, we present a patient in whom diagnosis of Alagille syndrome was done. It is important to be familiar with Alagille syndrome, so that its diagnosis can be suspected when a patient presents specific physical and morphological features, in addition to jaundice.

[20] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.343) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.