Alagille Syndrome 1

A number sign (#) is used with this entry because of evidence that Alagille syndrome can be caused by heterozygous mutation in the Jagged-1 gene (JAG1; 601920) on chromosome 20p12.

Description

Alagille syndrome is an autosomal dominant disorder that traditionally has been defined by a paucity of intrahepatic bile ducts, in association with 5 main clinical abnormalities: cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype (Li et al., 1997). Cholestasis is a direct consequence of the paucity of bile ducts. About 39% of patients also have renal involvement, mainly renal dysplasia (Kamath et al., 2012).

Turnpenny and Ellard (2012) reviewed the clinical features, diagnosis, pathogenesis, and genetics of Alagille syndrome.

Genetic Heterogeneity of Alagille Syndrome

Another form of Alagille syndrome (ALGS2; 610205) is caused by mutation in the NOTCH2 gene (600275).

Clinical Features

In addition to neonatal jaundice, features of this syndrome include the following: in the eye, posterior embryotoxon and retinal pigmentary changes; in the heart, pulmonic valvular stenosis as well as peripheral arterial stenosis; in the bones, abnormal vertebrae ('butterfly' vertebrae) and decrease in interpediculate distance in the lumbar spine; in the nervous system, absent deep tendon reflexes and poor school performance; in the facies, broad forehead, pointed mandible and bulbous tip of the nose and in the fingers, varying degrees of foreshortening (Watson and Miller, 1973; Alagille et al., 1975; Rosenfield et al., 1980). Histology of the liver demonstrates few intrahepatic bile ducts.

Shulman et al. (1984) described a kindred with 5 affected persons in 3 generations. Severity varied widely. In 2 sisters, neonatal jaundice, peripheral pulmonic stenosis, and characteristic facies including broad forehead, deep-set eyes, prominent nose, and pointed chin were features. One died at age 5 years of cirrhosis with portal hypertension and the other at 18 months of congestive heart failure. Their asymptomatic mother and maternal aunt had similar facial appearance, pulmonic stenosis, skeletal anomalies, and bilateral posterior embryotoxon. The maternal grandfather, who refused evaluation, had a similar appearance, history of liver disease, and a heart murmur.

Li et al. (1997) pictured clinical features of Alagille syndrome, including prominent forehead, pointed chin, posterior embryotoxon, and butterfly vertebra due to abnormal clefting of the vertebral bodies. Liver biopsy demonstrated multiple branches of the hepatic artery and portal vein in the portal tract without any accompanying bile ducts.

Based on 56 of their own observations, Krantz et al. (1997) showed that all affected persons have hepatic, cardiac, and facial abnormalities. Vertebral defects were found in 59%, renal in 23%, and ocular in 83% of examined patients. Two persons in their group had pancreatic insufficiency.

Lykavieris et al. (2001) reviewed the clinical outcome of 163 French patients with Alagille syndrome presenting in childhood. All patients had at least 3 of the 5 major clinical features. Overall, the prognosis was found to be worse in children presenting with neonatal cholestatic jaundice, although severe complications were possible even after late-onset liver disease. The authors argued for close lifelong follow-up.

Liver Involvement

In the 3 cases studied by Berman et al. (1981), cholestasis was not progressive and, although the SGPT was chronically elevated (122-520 units per liter), features of liver cell failure did not develop.

Riely et al. (1979) gave a useful differential diagnosis of familial intrahepatic cholestasis: Zellweger syndrome (see 214100), cholestasis-lymphedema syndrome (214900), Byler disease (211600), and cholestasis with defective formation of cholic acid (214950). Alpha-1-antitrypsin deficiency (613490) may present as neonatal cholestasis with a paucity of intrahepatic bile ducts.

In a longitudinal study, Dahms et al. (1982) sought to account for the pathologic hallmark of arteriohepatic dysplasia, namely, the paucity or absence of intrahepatic bile ducts. Liver biopsies under 6 months of age showed intrahepatic cholestasis and portal inflammation and in 2 of 5 cases giant cell transformation. None showed congenital absence of interlobular bile ducts; 3 of 5 had normal numbers of interlobular bile ducts, and 2 of 5 had paucity. Three of 5 showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later (ages 3 to 20 years) showed the characteristic paucity or absence. By this time cholestasis and inflammation had largely resolved but some fibrosis persisted. An acquired bile duct deficiency, possibly due to destructive inflammation of duct epithelium, was suggested. This disorder should be considered in all infants with cholestasis. The histologic diagnosis may be difficult or impossible in infancy. The diagnosis in that age group must rest on the syndromatic features.

Hepatocellular carcinoma has been reported in children with Alagille syndrome (Ong et al., 1986; Kaufman et al., 1987; Rabinovitz et al., 1989) and in an adult with Alagille syndrome without cirrhosis (Adams, 1986). Legius et al. (1990) speculated that loss of heterozygosity for a cell cycle-regulating gene rather than underlying chronic liver disease may be the explanation of liver carcinoma.

Craniofacial Involvement

Sokol et al. (1983) proposed that the facies seen in ALGS is nonspecific and secondary to congenital intrahepatic cholestasis from many causes.

Mueller et al. (1984) reviewed phenotypic features of 56 reported cases of Alagille syndrome and 7 of their own. They emphasized a characteristic facies with prominent forehead and chin with deep-set eyes and eye changes, usually asymptomatic: anterior chamber anomalies, which may be associated with eccentric or ectopic pupils, and retinal changes of chorioretinal atrophy and pigment clumping. Also see review by Mueller (1987).

Krantz et al. (1997) pictured the supposedly characteristic facies of 5 patients, including a mother and daughter and a father and daughter. Posterior embryotoxon in a father and daughter with ALGS was also pictured.

Kamath et al. (2002) reported 2 patients with mutation-proven ALGS who also had unilateral coronal craniosynostosis. They found no mutations in genes known to be associated with craniosynostosis and suggested that the JAG1 gene plays a role in cranial suture formation.

Kamath et al. (2003) studied 53 JAG1 mutation-positive relatives of 34 ALGS probands and found the characteristic facies to be the most highly penetrant feature.

Kamath et al. (2002) reported that the 49 clinical dysmorphologists they asked to examine a photographic panel of 18 pediatric and adult individuals with ALGS and other forms of congenital intrahepatic cholestasis correctly identified the ALGS facies 79% of the time, suggesting that the facies is specific to ALGS. Sokol (2004) and Kamath et al. (2004) exchanged letters regarding the evidence for and against a distinct facies in Alagille syndrome.

Skeletal Involvement

Rosenfield et al. (1980) described abnormalities in the shape and segmentation of vertebral bodies and short distal phalanges.

Ocular Involvement

Raymond et al. (1989) described Axenfeld anomaly in a 24-year-old black man with other signs of Alagille syndrome: congenital intrahepatic biliary atresia, systolic ejection murmur, short stature, butterfly vertebra at T-10, and hand changes (short ulnae, short scaphoids, and short distal phalanges).

From a study of 22 children with Alagille syndrome and 23 of their parents, Hingorani et al. (1999) concluded that Alagille syndrome is associated with a characteristic group of ocular findings without apparent serious functional significance and probably unrelated to fat-soluble vitamin deficiency. Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of Alagille syndrome, eliminating the need for extensive and invasive investigations. The most common ocular abnormalities in patients were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%, a previously unreported finding), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Microcornea was not associated with large refractive errors, and visual acuity was not significantly affected by these ocular changes. Ocular abnormalities, including posterior embryotoxon, iris abnormalities, and optic disc or fundus pigmentary changes, were detected in 1 parent in 36% of cases.

Kidney Involvement

LaBrecque et al. (1982) described 15 affected persons in 4 generations. They demonstrated renal dysplasia, renal artery stenosis, and hypertension in some.

Martin et al. (1996) described 3 children with Alagille syndrome, in 2 of whom a unilateral multicystic dysplastic kidney was detected by prenatal ultrasound; in the other, a solitary cortical cyst was found later in childhood. All had normal renal function, growth, and liver synthetic function but continued to have clinical and biochemical signs of cholestasis. Thus the authors concluded that Alagille syndrome should be included in the differential diagnosis of cystic kidney disorders associated with cholestatic liver disease.

In a retrospective study involving 187 patients with Alagille syndrome due to JAG1 mutations who had evaluable renal information, Kamath et al. (2012) found that 73 (39%) had a renal anomaly or disease. Most (58.9%) had renal dysplasia, followed by renal tubular acidosis (9.5%), vesicoureteral reflux (8.2%), urinary obstruction (8.2%), and chronic renal failure (5.4%). Renal dysplasia was defined by increased echogenicity of the kidneys, reflecting increased fibrous tissue. Many of the patients had impaired glomerular filtration rates (GFR). There were no genotype/phenotype correlations. Kamath et al. (2012) cited evidence indicating that the Notch signaling pathway is involved in kidney development, and suggested that renal involvement may be considered a disease-defining feature of Alagille syndrome.

Cardiovascular Involvement

Mueller et al. (1981) studied 7 patients in 5 families and reviewed 62 reported cases. Of the 69 cases, death from cardiovascular or hepatic complications occurred by age 5 years in 16.

Woolfenden et al. (1999) described 2 children with sporadic Alagille syndrome associated with moyamoya (252350). They interpreted this finding as indicating that Alagille syndrome is a vasculopathy.

Raas-Rothschild et al. (2002) found descriptions of abdominal coarctation of the aorta in 3 reported cases of ALGS. They described a fourth case in which, in addition to abdominal coarctation, there was right subclavian stenosis.

Lykavieris et al. (2003) reviewed the records of 174 patients with Alagille syndrome without liver failure and found that 22% had spontaneous or postprocedure bleeding in various organs. The authors suggested that patients with ALGS are at special risk for bleeding. Although they could not exclude a role for hypercholesterolemia, they speculated that abnormalities in the JAGGED1 signaling pathway may impair hemostatic function.

In a retrospective chart review of 268 individuals with ALGS, Kamath et al. (2004) found that 25 (9%) had noncardiac vascular anomalies or events, and that vascular accidents accounted for 34% of mortality in this cohort. The documented vascular anomalies included basilar and middle cerebral artery aneurysms, internal carotid artery anomalies, aortic aneurysms, and coarctation of the aorta; 1 patient had moyamoya disease. Kamath et al. (2004) concluded that vascular anomalies are a major cause of morbidity and mortality in patients with ALGS.

Rocha et al. (2012) reported a 10-year-old Caucasian girl with Alagille syndrome, confirmed by the finding of a truncating mutation in the JAG1 gene, who was found to have moyamoya syndrome on cerebral magnetic resonance angiography. The patient had no neurologic deficits. Features of Alagille syndrome included posterior embryotoxon, eccentric pupils, peripheral pulmonary stenosis, and facial dysmorphism. Bilirubin was normal, but cholesterol was elevated. Rocha et al. (2012) reviewed the several cases of moyamoya syndrome previously reported in Alagille syndrome, noting that it can be a feature of the disorder.

Other Features

In a 36-day-old male with typical features of Alagille syndrome, Rodriguez et al. (1991) found associated caudal dysplasia sequence: imperforate anus, rectourethral fistula, lumbosacral abnormalities, and dysplastic right kidney.

Bucuvalas et al. (1993) concluded that growth-retarded children with Alagille syndrome are insensitive to growth hormone (GH; 139250). They thought that the growth disturbance and metabolic defects may be due in part to failure to increase IGF1 (147440) concentrations in response to GH, implying that such patients may benefit from IGF1 treatment.

In a 19-year-old woman with Alagille syndrome diagnosed at the age of 8 years, Kato et al. (1994) described papillary thyroid carcinoma (see 188550) with multiple lung metastases. They reviewed 12 reported cases of hepatocellular carcinoma. Development of carcinoma was as early as age 2 years and as late as 48 years.

Ho et al. (2000) described a 3-year-old Asian boy with Alagille syndrome who had severe generalized xanthomas, including oral xanthomas, and marked hypodontia.

Kamath et al. (2002) reported the presence of supernumerary digital flexion creases, a finding reported in less than 1% of the general population, in 16 of 46 (35%) ALGS probands examined.

Diagnosis

Diagnosis in a proband is made if bile duct paucity is accompanied by 3 of the main 5 clinical criteria (Alagille et al., 1987). It has been suggested that family members should be considered affected if they express any of the 5 main clinical features (variable expressivity) (Watson and Miller, 1973; Dhorne-Pollet et al., 1994).

Gonioscopy with demonstration of embryotoxon is a valuable way to make the diagnosis in mildly affected persons (Romanchuk et al., 1981).

In a review of the Alagille syndrome, Turnpenny and Ellard (2012) noted that the diagnosis can be difficult in some patients who do not show unequivocal classic features of the disorder.

Population Genetics

Danks et al. (1977) gave an estimated minimum population frequency of 1 in 70,000 births, when ascertained by the presence of neonatal jaundice. Li et al. (1997) considered the true incidence most likely higher.

Inheritance

Alagille syndrome is transmitted in an autosomal dominant pattern of inheritance with incomplete penetrance (summary by Turnpenny and Ellard, 2012).

Henriksen et al. (1977) reported affected father and daughter, Riely et al. (1979) and Rosenfield et al. (1980) reported father and son, and LaBrecque and Mitros (1982) described the condition in 4 generations of 1 kindred.

Although autosomal dominant inheritance with reduced penetrance had been suggested by the analysis of a limited number of families, no statistical analysis had been performed prior to that done by Dhorne-Pollet et al. (1994). They analyzed 33 families collected through 43 probands. They corroborated the autosomal dominant inheritance and concluded that penetrance is 94% and that 15% of cases are sporadic. Expressivity was variable; 26 persons (15 persons and 11 sibs) were identified as presenting minor forms of the disease. Because the individual manifestations are rare in the general population, Dhorne-Pollet et al. (1994) assumed that the presence of only 1 feature (the facies being excluded) was sufficient for considering a family member to be affected with Alagille syndrome. The frequency of butterfly-like vertebrae is unknown but must be rare. Embryotoxon is the symptom of Alagille syndrome most frequent in the general population, affecting 8 to 10%. Among the 33 families, mothers were affected in 12 families and fathers were affected in only 3.

To determine the rate of new mutations and to develop criteria for detecting the disorder in parents, Elmslie et al. (1995) systematically investigated parents in 14 families with an affected child. Clinical examination was supplemented by liver function tests, echocardiography, radiographic examination of the spine and forearm, ophthalmologic assessment, and chromosome analysis. Six parents had typical anomalies in 2 or more systems, pointing to the presence of autosomal dominant inheritance. In 3 cases, the father was the affected parent, and in 3 the mother was affected. In only one case had the affected parent previously suspected that he was affected. All affected parents had posterior embryotoxon and at least one other major syndromic feature. Five had abnormalities of the spine and eye. In 3, midline notches on the vertebral endplates were present, representing fused butterfly vertebrae. Four also had a short ulna. Two had anomalous optic discs and a pigmentary retinopathy. The mother in one family and the father in a second had a history of unexplained jaundice in infancy and recovered spontaneously. Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counseling.

In a study of 53 JAG1 mutation-positive relatives of 34 ALGS probands, Kamath et al. (2003) found that 25 of the relatives (including 2 with no features of ALGS) did not meet the accepted clinical criteria. Seventeen had mild features found only after targeted evaluation; and 11 were readily diagnosed with ALGS. The frequency of cardiac and liver disease was notably lower in relatives than in probands, characterizing the milder end of the phenotypic spectrum.

Cytogenetics

Byrne et al. (1986) described arteriohepatic dysplasia in a small-for-gestational age white female infant who had deletion of 20p11.2. The child had multiple minor anomalies and severe jejunal stenosis similar to the findings in 2 previously reported instances of 20p11.2 deletions. In addition, mild peripheral pulmonic stenosis, skeletal anomalies, and cholestasis with paucity of intrahepatic bile ducts were observed. The possibility of a gene for arteriohepatic dysplasia at this site on chromosome 20 was raised by the authors.

Mujica et al. (1989) described Alagille syndrome in association with an apparently balanced translocation t(4;14)(q21;q21).

Schnittger et al. (1989) found an interstitial deletion of chromosome 20 in a 20-year-old female with typical signs. Considering the clinical similarity of 9 further cases with a 20p deletion reported in the literature, Schnittger et al. (1989) proposed that AWS is a 'contiguous gene syndrome' provisionally located in the area 20p12.1-p11.23.

In an 8-year-old boy with arteriohepatic dysplasia, Zhang et al. (1990) demonstrated deletion of 20p12.3-p11.23. Legius et al. (1990) found deletion of 20p11.2 in a patient with this syndrome. They emphasized the peculiar face with parietal bossing and small upturned nose. Anad et al. (1990) added 5 cases of 20p deletion to the 10 already known. Four had the features of Alagille syndrome. Furthermore, they observed interstitial deletion of 20p in a mother and son, both of whom had features of Alagille syndrome. Teebi et al. (1992) described an Arab boy with this syndrome associated with a de novo deletion of chromosome 20: 46,XY,del(20)(p11.2).

By high resolution banding techniques, nonradioactive in situ hybridization, and molecular studies for allelic losses, Desmaze et al. (1992) found no evidence of microdeletion of chromosome 20 in 14 patients with Alagille syndrome.

Studying a case of ALGS with microdeletion in the short arm of chromosome 20 encompassing bands p12.3 to p11.23, Deleuze et al. (1994) showed that 3 genes were outside the deletion and thus excluded as candidate genes: paired box-1 (PAX1; 167411), cystatin C (CST3; 604312), and hepatic nuclear factor-3-beta (HNF3B; 600288).

Spinner et al. (1994) described a cytologically balanced t(2;20) in a 2-generation family with Alagille syndrome. The family was identified through a proband with all 5 of the clinical criteria for diagnosis of the disorder; clinical assessment of the family identified 2 other affected individuals, who had less severe disease. Cosegregation of the translocation with the clinical disorder indicated that the cytogenetic rearrangement involved the ALGS locus. Spinner et al. (1994) constructed hybrids from the patients' cell lines and by studying these were able to localize the translocation breakpoint distal to D20S61 and D20S56 within band 20p12. Characteristic facies in the 15-year-old proband and her subclinically affected father was illustrated, showing prominent forehead, triangular facies, deep-set eyes, and a small, anteriorly pointed chin. The proband's sister had hepatomegaly without jaundice and a systolic murmur in infancy and had the same facial features. Failure to thrive was present at 6 months of age. Biochemical evaluation at 2 years of age demonstrated mildly elevated transaminases and a moderately elevated alkaline phosphatase. Eye examination demonstrated posterior embryotoxon. The father demonstrated biochemical liver abnormalities, including elevated transaminases and hypercholesterolemia, but no clinically evident liver disease.

By mapping with microsatellite markers in the Alagille region, Deleuze et al. (1994) and Rand et al. (1995) concluded that submicroscopic deletions are rarely the basis of Alagille syndrome in cytogenetically normal patients.

Li et al. (1996) described a 6-year-old boy with Alagille syndrome and hypoplastic corpus callosum. This patient had interstitial deletion of the 20p12.2-p11.23 (or 20p13-p12.2) segment due to segregation of maternal ins(7;20)(q11.23;p11.23p12.2 or p12.2p13). His elder brother, who died of liver failure and tetralogy of Fallot, had not been studied cytogenetically. Because the maternal phenotype was normal, Li et al. (1996) concluded that the gene for Alagille syndrome would be located within the deletion extent rather than at the insertion breakpoints.

Krantz et al. (1997) reported only 2 visible rearrangements (1 apparently balanced translocation and 1 deletion) in a group of 56 persons, and only 1 more patient was found to have submicroscopic deletion within 20p12. A low incidence of deletions argued for a single gene etiology of the syndrome.

Li et al. (1997) estimated that less than 7% of patients with Alagille syndrome have deletions of 20p12.

Mapping

Hol et al. (1995) performed linkage analysis in a 3-generation family with ALGS in which the affected members had a normal karyotype. A lod score of 2.96 was obtained with D20S27 at no recombination. Combining D20S27 and D20S61 to a single highly informative locus resulted in a maximum lod score of 3.56 at theta = 0.0. Haplotype analysis positioned ALGS between D20S59 and D20S65, markers that define an interval of about 40 cM. Allelic loss was not observed for the tested markers and no abnormalities were detected in the PAX1 gene (167411), which because of its location at 20p11.2 was considered a candidate gene for ALGS.

Pollet et al. (1995) established a YAC contig that spans the ALGS region that should be valuable for cloning candidate genes and searching for DNA polymorphisms segregating with the disorder.

Molecular Genetics

Oda et al. (1997) and Li et al. (1997) demonstrated that Alagille syndrome is caused by mutations in the human homolog of Jagged-1 (JAG1; 601920), which encodes a ligand for NOTCH1 (190198). Oda et al. (1997) generated a cloned contig of the critical region revealed by cytogenetic deletions and used fluorescence in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region they identified JAG1, the human homolog of rat Jagged-1, which encodes a ligand for the NOTCH1 receptor. Cell-cell Jagged/Notch interactions are critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon/intron structure of JAG1 allowed them to perform detailed mutational analysis of DNA samples from non-deletion ALGS patients, revealing 3 frameshift mutations, 2 splice donor site mutations, and 1 mutation abolishing RNA expression from the altered allele. They concluded that ALGS is caused by haploinsufficiency of JAG1.

Li et al. (1997) mapped the human JAG1 gene to the Alagille syndrome critical region within 20p12, and demonstrated 4 distinct coding mutations in JAG1 in 4 Alagille syndrome families.

Yuan et al. (1998) analyzed the JAG1 gene in 8 Alagille syndrome families. Four categories of mutations were identified: (1) 4 frameshift mutations in exons 9, 22, 24, and 26 were exhibited respectively in affected individuals in 4 ALGS families, which resulted in moving the translational frame of JAG1; (2) 1 nonsense mutation, a 1-bp substitution in exon 5 of the EGF-like repeat domain, was detected in 2 unrelated ALGS families, which altered codon 235 from arginine to stop; (3) 1 acceptor splice site mutation in exon 5 was found in a sporadic patient; and (4) a 1.3-Mb deletion, which included the entire JAG1 gene, was found in another patient. All of the mutations were present in heterozygous form, supporting the dominant inheritance of Alagille syndrome.

Giannakudis et al. (2001) detected parental mosaicism for a JAG1 mutation in 4 of 51 families where mutations had been identified in the ALGS patients and where parental DNA was available. In each of the 4 families, the parent with mosaicism exhibited only the characteristic face with or without an embryotoxon posterior but no other features of ALGS. One case was observed where mosaicism was present in the patient himself, reflecting a somatic mosaicism due to a deletion of the JAG1 gene. Giannakudis et al. (2001) suggested that the high prevalence of parental mosaicism be taken into account in diagnosis, genetic counseling, and prognosis in ALGS. They also suggested that the high failure rate in mutation detection in ALGS patients may in part be due to mosaicism.

In a patient with abdominal aortic coarctation with right subclavian stenosis, Raas-Rothschild et al. (2002) identified a deletion mutation in the JAG1 gene (601920.0013).

Kamath et al. (2002) reported monozygotic twins with Alagille syndrome who were concordant for a mutation in JAG1 (601920.0014) but discordant for a clinical phenotype. One twin had severe pulmonary atresia with mild liver involvement, whereas the other had tetralogy of Fallot and severe hepatic involvement that required a liver transplant.

El-Rassy et al. (2008) screened an ALGS proband and his JAG1 mutation-positive father and sister for additional mutations in the NOTCH2 and HEY2 (604674) genes but found no additional mutations. The proband had severe liver failure, mild pulmonary stenosis, and dysmorphic facial features. His 7-year-old sister had the same dysmorphic facial features, mild developmental delay, and elevated liver function enzymes, and his father had only mild dysmorphic facial features and mild retinitis pigmentosa. El-Rassy et al. (2008) suggested that other genes in the JAG/NOTCH pathway might be implicated in the diverse phenotypes seen in this family.

Among 230 patients with tetralogy of Fallot, Rauch et al. (2010) found that 3 (1.3%) had Alagille syndrome associated with JAG1 mutations.

Pathogenesis

Boyer et al. (2005) studied RNA products obtained from liver tissue of 5 patients with ALGS and from lymphoblastoid cell lines of 24 patients with ALGS. Mutant JAG1 transcripts were obtained in different relative amounts from RNAs with missense mutations or in-frame deletions, and from 19 of 21 RNAs with premature termination mutations. Results from lymphoblastoid cell lines correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of an affected 23-week-old fetus with a truncation mutation. The findings suggested that most mutant transcripts with truncation mutations escape nonsense-mediated mRNA decay and could lead to the synthesis of soluble forms of JAG1. Although haploinsufficiency is the main molecular mechanism responsible for ALGS, Boyer et al. (2005) concluded that the stability of most mutant JAG1 RNAs could also lead to the production of abnormal JAG1 proteins acting in a dominant-negative manner.

Boyer-Di Ponio et al. (2007) found that ALGS fetal fibroblasts and mouse fibroblasts expressing JAG1 with missense or nonsense mutations formed a network of cord-like structures in culture, in contrast to the even cell distribution of wildtype human or mouse fibroblasts. Pharmacologic inhibition of Notch signaling in wildtype cells resulted in the same phenotype. Coexpression of the mutant JAG1 proteins inhibited activation of a Notch reporter construct by wildtype JAG1. Boyer-Di Ponio et al. (2007) concluded that some ALGS-associated mutant JAG1 proteins can function as dominant-negative inhibitors of Notch signaling.

Animal Model

In a mouse model that mimics the hepatic phenotype of human Alagille syndrome, Schaub et al. (2018) demonstrated that transdifferentiation of hepatocytes in the mouse liver can build the biliary system that failed to form in development. In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefined hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system. In contrast to bile duct development, Schaub et al. (2018) showed that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signaling. The authors found that TGF-beta (TGFB; 190180) signaling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, Schaub et al. (2018) showed that TGF-beta signaling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes.