Mutations In JAG1 Research Articles

Requirement for Jagged1-Notch2 signaling in patterning the bones of the mouse and human middle ear

Whereas Jagged1-Notch2 signaling is known to pattern the sensorineural components of the inner ear, its role in middle ear development has been less clear. We previously reported a role for Jagged-Notch signaling in shaping skeletal elements derived from the first two pharyngeal arches of zebrafish. Here we show a conserved requirement for Jagged1-Notch2 signaling in patterning the stapes and incus middle ear bones derived from the equivalent pharyngeal arches of mammals. Mice lacking Jagged1 or Notch2 in neural crest-derived cells (NCCs) of the pharyngeal arches display a malformed stapes. Heterozygous Jagged1 knockout mice, a model for Alagille Syndrome (AGS), also display stapes and incus defects. We find that Jagged1-Notch2 signaling functions early to pattern the stapes cartilage template, with stapes malformations correlating with hearing loss across all frequencies. We observe similar stapes defects and hearing loss in one patient with heterozygous JAGGED1 loss, and a diversity of conductive and sensorineural hearing loss in nearly half of AGS patients, many of which carry JAGGED1 mutations. Our findings reveal deep conservation of Jagged1-Notch2 signaling in patterning the pharyngeal arches from fish to mouse to man, despite the very different functions of their skeletal derivatives in jaw support and sound transduction.

Acute on Chronic Liver Failure and Urgent Orthotopic Liver Transplantation in an Adult with Alagille Syndrome

Alagille syndrome is an autosomal dominant syndrome marked by a paucity of interlobular bile ducts with cholestasis, and whose features can include butterfly vertebrae, dysmorphic facies, cardiac and ocular anomalies. Most patients are symptomatic during childhood. As adult patients may require elective liver transplant for cirrhosis and intractable pruritus, liver failure is uncommon in these patients. We present a case of liver failure in an adult with Alagille syndrome. A 32-year-old man with known Alagille syndrome was admitted to the hospital with progressive jaundice and RUQ pain. At that time his MELD was 24 and he was referred for liver transplant evaluation. A month later, he was admitted for hematemesis and hepatic encephalopathy. He had a complicated hospital course with worsening encephalopathy, hepatorenal syndrome (requiring dialysis), and septic shock due to Streptococcus viridans requiring pressors. His peak MELD score during this hospitalization was 42(total bilirubin 47.5, Cr 5, INR 2.0). A CDC high risk liver became available and he underwent an orthotopic liver transplant. This was complicated by bacterial peritonitis from an infected hematoma. However, he recovered well after treatment of his peritonitis, and LFTs were normal one month post-transplant. Allagile syndrome occurs in 1 in 70,000 live births from a JAG1 or NOTCH2 mutation. They have paucity or stenotic bile ducts with progressive cholestasis in 95%, and cirrhosis in more than 20% of cases. Initial treatment includes ursodeoxycholic acid, cholestyramine, fat soluble vitamins and nutrition support. However, 21-31% patients will require liver transplant for severe xanthomatosis, intractable pruritus, and portal hypertension. Most liver transplants are done in the pediatric group. Only 9.7% patients had their first liver transplant beyond 18 years old, and are done electively for cirrhosis and intractable pruritus. Only a few cases were reported due to acute liver failure requiring an urgent transplant, similar to our patient. Alagille syndrome patients may require liver transplantation, usually during childhood. In some cases, transplant may be required in adulthood due to liver cirrhosis and intractable pruritis, and is mostly elective. Liver failure is uncommon in these patients.

Target gene sequence capture and next generation sequencing technology to diagnose four children with Alagille syndrome

To make genetic diagnosis of Alagille syndrome (ALGS) patients using target gene sequence capture and next generation sequencing technology. Target gene sequence capture and next generation sequencing were used to detect ALGS gene of 4 patients. They were hospitalized at the Affiliated Hospital, Capital Institute of Pediatrics between January 2014 and December 2015, referred to clinical diagnosis of ALGS typical and atypical respectively in 2 cases. Blood samples were collected from patients and their parents and genomic DNA was extracted from lymphocytes. Target gene sequence capture and next generation sequencing was detected. Sanger sequencing was used to confirm the results of the patients and their parents. Cholestasis, heart defects, inverted triangular face and butterfly vertebrae were presented as main clinical features in 4 male patients. The first hospital visiting ages ranged from 3 months and 14 days to 3 years and 1 month. The age of onset ranged from 3 days to 42 days (median 23 days). According to the clinical diagnostic criteria of ALGS, patient 1 and patient 2 were considered as typical ALGS. The other 2 patients were considered as atypical ALGS. Four Jagged 1(JAG1) pathogenic mutations were detected. Three different missense mutations were detected in patient 1 to patient 3 with ALGS(c.839C>T(p.W280X), c. 703G>A(p.R235X), c. 1720C>T(p.V574M)). The JAG1 mutation of patient 3 was first reported. Patient 4 had one novel insertion mutation (c.1779_1780insA(p.Ile594AsnfsTer23)). Parental analysis verified that the JAG1 missense mutation of 3 patients were de novo. The results of sanger sequencing was consistent with the results of the next generation sequencing. Target gene sequence capture combined with next generation sequencing can detect two pathogenic genes in ALGS and test genes of other related diseases in infantile cholestatic diseases simultaneously and presents a high throughput, high efficiency and low cost. It may provide molecular diagnosis and treatment for clinicians with good clinical application prospects.

THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome.

Background & AimsAlagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.MethodsWe performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.ResultsWe identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions.ConclusionsBased on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

Alagille Syndrome Mimicking Biliary Atresia in Early Infancy.

Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we aimed to identify JAG1 mutations in newborns with proven biliary atresia (n = 72). Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1. No mutations were found in the remaining 67 patients. All “biliary atresia” carriers of JAG1 null mutations developed typical Alagille syndrome at the age of three years. Our data do not support association of biliary atresia with JAG1 mutations, at least in Czech patients. Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.

JAG1 Mutation Spectrum and Origin in Chinese Children with Clinical Features of Alagille Syndrome.

Alagille syndrome is an autosomal dominant disorder that results from defects in the Notch signaling pathway, which is most frequently due to JAG1 mutations. This study investigated the rate, spectrum, and origin of JAG1 mutations in 91 Chinese children presenting with at least two clinical features of Alagille syndrome (cholestasis, heart murmur, skeletal abnormalities, ocular abnormalities, characteristic facial features, and renal abnormalities). Direct sequencing and/or multiplex-ligation-dependent probe amplification were performed in these patients, and segregation analysis was performed using samples available from the parents. JAG1 disease-causing mutations were detected in 70/91 (76.9%) patients, including 29/70 (41.4%) small deletions, 6/70 (8.6%) small insertions, 16/70 (22.9%) nonsense mutations, 8/70 (11.4%) splice-site mutations, 6/70 (9.4%) missense mutations, and 5/70 (7.1%) gross deletions. Of the mutations detected, 45/62 (72.6%) were novel, and almost all were unique, with the exception of c.439C>T, c.439+1G>A, c.703C>T, c.1382_1383delAC, c.2698C>T, and c.2990C>A, which were detected in two cases each; three cases exhibited entire gene deletions. A majority (69.2%) of the point and frameshift mutations could be detected by the sequencing of eleven exons (exons 3, 5, 6, 11, 14, 16, 18, 21, and 23–25). The mutation detection rate was 50.0% (10/20) in atypical cases that only presented with two or three clinical features of Alagille syndrome. Segregation analysis revealed that 81.1% (30/37) of these mutations were de novo. In conclusion, JAG1 mutations are present in the majority of Chinese pediatric patients with clinical features of Alagille syndrome, and the mutations concentrate on different exons from other reports. Genetic study is important for the diagnosis of atypical Alagille syndrome in Chinese patients.

Immune dysregulation in Alagille syndrome: A new feature of the evolving phenotype

Alagille syndrome (ALGS) is a rare autosomal dominant, multi-system disease caused by mutations in one of two NOTCH signaling pathway genes. Mutations in JAG1 are found in more than 94% of patients, with associated Jagged1 defects. We previously showed that CD46, which is a complement and immune regulator, regulates NOTCH expression during T cell activation after binding to C3b/C4b. We have identified 25% of our ALGS cohort with frequent infections and studied a subgroup of 4 in detail who were not showing current features of infections in order to show if Jagged1 abnormalities could affect immune function. We used cytometric bead arrays and FACS to measure cytokines and cell membrane expression. Resting and activated T cells were studied in both low and high IL-2 concentration to assess the TH1 ability to shift from INFγ to IL-10 production. In vitro initial PBMC cell population and subpopulation assessment were normal but further assessment of the lymphocytes revealed that while NOTCH1 expression and regulation was normal on resting TH1, Jagged1 expression was exaggerated. Resting TH1 cells from some patients exhibited high CD132 levels. Upon activating T cells, TH1 cells managed to produce TNF but failed to produce sufficient IFNγ levels (in two patients TH1 produced no IFNγ). TH2 exhibited exaggerated response with high IL-4 and IL-5 levels. TH1 were unable to down-regulate CD127, resulting in prolonged immune activation, and failed to shift from IFNγ to IL-10 production maintaining high IL-2 levels suggesting an impaired T cell response. Disturbed CD46-Jagged1 interaction may explain recurrent infections among ALGS patients, and could predispose to Th2-driven conditions such as asthma, eczema, food allergies and airway atopy and otitis media. The ALGS description could now be extended to include immune dysregulation.

Clinical features, outcomes, and genetic analysis in Korean children with Alagille syndrome.

Alagille syndrome (AGS) is a multisystem autosomal dominant disorder that affects the liver, heart, eyes, face, bone, and other organs. AGS is caused by mutations in one of two genes, JAG1 or NOTCH2. We evaluated clinical features, outcomes, and the presence of JAG1 and NOTCH2 mutations in Korean children with AGS. Between January 1997 and December 2013, 19 children were diagnosed with AGS at Asan Medical Center, Seoul, Korea. Their clinical features, outcomes, and JAG1 and NOTCH2 mutation status were retrospectively analyzed. The prevalence of clinical features in the 19 patients was as follows: dysmorphic facial features, 100% (n = 19); liver symptoms, 89% (n = 17); cardiac symptoms, 95% (n = 18); ophthalmologic symptoms, 67% (n = 10); skeletal deformities, 47% (n = 9); and renal symptoms, 21% (n = 4). JAG1 mutations were identified in 14 patients. The 13 different JAG1 mutations, seven of which were novel, included four deletions, three insertions, two missense mutations, three nonsense mutations, and one indel mutation. No NOTCH2 mutations were found. Two patients who received liver transplantation due to liver failure were still alive. Two patients died of comorbidities related to AGS: one of cardiac failure and one of hepatic failure. This study describes the clinical characteristics of 19 Korean AGS patients with seven novel JAG1 mutations. Neonatal cholestatic jaundice was the most common initial presenting symptom; thus the presence of neonatal cholestasis warrants screening for syndromic features of AGS. Complex heart anomalies and progressive liver dysfunction resulted in significant morbidity and mortality in AGS.

Alagille syndrome and a JAG1 mutation: 41 cases of experience at a single center.

PurposeAlagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis.MethodsWe conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013.ResultsThe first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001).ConclusionThe group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome.

Alagille syndrome: Is it always cholestasis?

Background: Alagille syndrome (AS) is a rare multisystemic AD disease caused by an alteration of NOTCH 2 pathway (prevalently due to JAG1 mutation). It causes chronic cholestasis which is a frequent indication for pediatric liver transplantation. Diagnosis is suspected if chronic cholestasis is accompanied by at least three of the following features: congenital heart disease, vertebral segmentation anomalies, characteristic facies, posterior embryotoxon. Here we describe a patient with a novel mutation without chronic cholestasis.

Splenic Hamartomas in Alagille Syndrome: Case Report and Literature Review

Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral, ocular, and renal abnormalities. We present a unique autopsy case of an 18-year-old female with Alagille syndrome and splenic hamartomas. Autopsy findings included growth restriction, Tetralogy of Fallot, paucity of intrahepatic bile ducts, end-stage renal disease with mesangiolipidosis, and splenomegaly with two well-circumscribed, splenic tumors. Histologic findings of the splenic tumors revealed disorganized vascular channels lined by cells without cytologic atypia. Immunohistochemical analysis demonstrated CD8+CD31+ endothelial cells, consistent with splenic hamartomas. In summary, Alagille syndrome is a rare genetic disorder characterized by JAG1 mutations and disrupted Notch signaling. Review of the literature highlights the importance of Notch signaling in vascular development and disorders. However, to our knowledge this is the first description of splenic hamartomas in Alagille syndrome.

Microarray Data Reveal Relationship between Jag1 and Ddr1 in Mouse Liver

Alagille syndrome is an autosomal dominant disorder involving bile duct paucity and cholestasis in addition to cardiac, skeletal, ophthalmologic, renal and vascular manifestations. Mutations in JAG1, encoding a ligand in the Notch signaling pathway, are found in 95% of patients meeting clinical criteria for Alagille syndrome. In order to define the role of Jag1 in the bile duct developmental abnormalities seen in ALGS, we previously created a Jag1 conditional knockout mouse model. Mice heterozygous for the Jag1 conditional and null alleles demonstrate abnormalities in postnatal bile duct growth and remodeling, with portal expansion and increased numbers of malformed bile ducts. In this study we report the results of microarray analysis and identify genes and pathways differentially expressed in the Jag1 conditional/null livers as compared with littermate controls. In the initial microarray analysis, we found that many of the genes up-regulated in the Jag1 conditional/null mutant livers were related to extracellular matrix (ECM) interactions, cell adhesion and cell migration. One of the most highly up-regulated genes was Ddr1, encoding a receptor tyrosine kinase (RTK) belonging to a large RTK family. We have found extensive co-localization of Jag1 and Ddr1 in bile ducts and blood vessels in postnatal liver. In addition, co-immunoprecipitation data provide evidence for a novel protein interaction between Jag1 and Ddr1. Further studies will be required to define the nature of this interaction and its functional consequences, which may have significant implications for bile duct remodeling and repair of liver injury.

Notch signaling and new therapeutic options in liver disease

Notch signaling is a crucial determinant of cell fate decision during development and disease in several organs. Notch effects are strictly dependent on the cellular context in which it is activated. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis. Recent advances have shed light on Notch as a critical player in liver regeneration and repair, as well as in liver metabolism and inflammation and cancer. Notch signaling is finely regulated at several levels. The complexity of the pathway provides several possible targets for development of therapeutic agents able to inhibit Notch. Recent reports have shown that persistent activation of Notch signaling is associated with liver malignancies, particularly hepatocellular with stem cell features and cholangiocarcinoma. These novel findings suggest that interfering with the aberrant activation of the Notch pathway may have therapeutic relevance. However, further studies are needed to clarify the mechanisms regulating physiologic and pathologic Notch activation in the adult liver, to better understand the mechanistic role(s) of Notch in liver diseases and to develop safe and specific therapeutic agents.

JAG1 Mutation in a patient with deletion 22q11.2 syndrome and tetralogy of Fallot

Deletion 22q11.2 (del22q11.2) syndrome, also known as DiGeorge/Velo-cardio-facial syndrome (DG/VCFS), and Alagille syndrome are genetic disorders characteristically associated with congenital heart defects (CHDs). We report on a patient with tetralogy of Fallot (TOF) and clinical features of DG/VCFS, hemizygous for del22q11.2 and heterozygous for the 2810G > A (p.Arg937Gln) mutation in the JAG1 gene associated with Alagille syndrome. The clinical features of del22q11.2 syndrome are present in the patient, including facial anomalies, typical TOF, speech delay with hypernasal voice, and learning difficulties. TOF and mild hepatic involvement, consisting of slightly elevated aminotransferase conjugated bilirubin levels, were the only features of Alagille syndrome in our patient. The anatomic type of TOF displayed no distinctive recognizable pattern for either DG/VCFS or Alagille syndrome. It is likely that hemizygosity of the TBX1 gene was causally related to TOF in this patient, although a synergistic pathogenic role of the JAG1 gene mutation in causing the heart defect cannot be excluded. JAG1 mutations have been previously detected in patients with nonsyndromic TOF and recent molecular evidence supports the cumulative effect of multiple genetic defects in the etiology of human malformations. We hypothesize that a similar mechanism could be present in this patient with del22q11.2 syndrome associated with a JAG1 missense mutation acting as possible modifier factor for TOF.

Reprint of: Disrupting Jagged1–Notch signaling impairs spatial memory formation in adult mice

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1+/−) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1–Notch signaling is critical for memory formation in the adult brain.

Disrupting Jagged1–Notch signaling impairs spatial memory formation in adult mice

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1+/−) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1–Notch signaling is critical for memory formation in the adult brain.

Neural crest specific ablation of Jagged1 results in aberrant osteoblast differentiation and maxillary bone development

Maxillary hypoplasia results from insufficient growth of the upper jaw bone which affects mastication, respiration and communication. This results from either extrinsic restriction due to premature cranial base suture fusion (eg Apert Syndrome) or from intrinsic growth deficiency of the maxilla (eg Alagille Syndrome). The maxillary bone is formed through intramembranous ossification of neural crest cell derived mesenchyme. Conditional deletion of Jagged1 in the cranial neural crest cells (CNC) using Wnt1‐Cre (Jag1CKO) recapitulated the maxillary hypoplasia phenotype in Alagille Syndrome patients, who have JAGGED1 mutations. Jag1CKO mice die by P21 due to starvation secondary to severe maxillary hypoplasia. Analysis of the maxilla using qPCR and immunohistochemistry on Jag1CKO mice from e14 to e18 revealed reduced expression of early and late markers of osteoblast differentiation. In vitro bone mineralization cultures demonstrated that Jag1CKO maxillary mesenchymal cells have decreased mineralization potential and a diminished induction of osteoblast differentiation markers. In addition, lack of Jagged1 signaling in the maxilla resulted in disregulated BMP and TGFβ signaling pathways. These data suggest that Jagged1 signaling in CNC is required during osteoblast differentiation and that down‐stream targets of Jagged1 signaling include the BMP and TGFβ pathways.

Adult-onset renal failure in a family with Alagille syndrome with proteinuria and a novel JAG1 mutation.

Alagille syndrome (AGS) is an autosomal-dominant multi-organ disorder involving the liver, heart, eyes, face and skeleton. In addition, various renal abnormalities have also been reported in several cases. We describe a patient with a novel frameshift mutation in exon 12 of the JAG1 gene who presented with chronic renal failure. In this family, five members of three generations had clinical features implicated in AGS. Three members had adult-onset renal dysfunction with proteinuria, and two of them required haemodialysis therapy. AGS should be considered in the differential diagnosis of proteinuric renal disease, even in adult patients.

Missexpression of Human JAGGED1 Causes Disorganization of The Biliary Tree in Zebrafish Consistent With a Biliary Atresia Phenotype

Biliary atresia (BA) is a progressive, fibro-obliterative cholangiopathy of infants, which if left untreated is fatal. The pathogenesis of BA is not fully understood but may involve dysregulation of hepatic progenitor/stem cells (HPSC) during development of the biliary tree. Recent data indicate that ductular proliferation, a pathologic hallmark of BA, represents massive expansion of HPSC marked with an epithelial stem cell marker GCTM5 (Stamp et al, Stem Cells 2012). Alagille syndrome (AGS), a congenital disorder marked by a paucity of bile ducts, is caused by haploinsufficiency of JAGGED1 (JAG1), a gene that encodes a Notch pathway ligand critical for HPSC proliferation and differentiation at the onset of biliary organogenesis. Kohsaka et al reported that missense mutations in JAG1 occur in a subset of cases of BA and are associated with poorer prognosis (Hepatology 2004). Preliminary in vitro data indicate that these BA-associated JAG1 mutations result in increased Notch activity in contrast to AGS possibly through enhanced subcellular trafficking of ligand. We, therefore, hypothesized that in vivo misexpression of wild-type human JAG1 in transgenic zebrafish would result in increased Notch pathway activation, thus, disrupting biliary organogenesis leading to a disorganized biliary tree.

Síndrome de Alagille

Alagille syndrome (AS) is a multisystemic disease autosomal dominant, with variable expression. The major clinical manifestations are: chronic cholestasis, congenital heart disease, posterior embryotoxon in the eye, characteristic facial phenotype, and butterfy vertebrae. AS is caused by mutations in JAGGED1 (more than 90%) and in NOTCH2. Differential diagnosis include: infections, genetic-metabolic diseases, biliary atresia, idiopathic cholestasis. Cholestasis, pruritus and xanthomas have been successfully treated with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). In certain cases, partial external biliary diversion has also proved successful. Liver transplantation is indicated in children with cirrhosis and liver failure.