Alagille syndrome (AGS)

2005-10-01   Michçle Meunier-Rotival , Michelle Hadchouel 



Alagille syndrome (AGS)


Alagille-Watson syndrome (AWS) , Arteriohepatic dysplasia (AHD) , Cholestasis with peripheral pulmonary stenosis , Hepatic ductular paucity, syndromatic


syndrome associating 5 major features (complete syndrome) : paucity of interlobular bile ducts, pulmonary artery stenosis, butterfly-like vertebrae, posterior embryotoxon and a peculiar face. Only the 2 first ones are symptomatic. Incomplete syndrome is very frequent. Other features have been described involving kidney, cardiac and vascular anomalies including tetralogy of Fallot, ear, pancreas, intestine etc


autosomal dominant with a highly variable expressivity and nearly complete penetrance ; frequency is about 1\/70,000-100,000 live newborns ; 60-70% are sporadic cases.


118450 , 610205




52 Alagille syndrome




Phenotype and clinics

  • liver : jaundice, pruritus, xanthomas, bile duct paucity, biochemical cholestasis and hypercholesterolemia. Liver transplantation is performed in about 25% cases.
  • cardiovascular system : peripheral pulmonary stenosis, coarctation of aorta, tetralogy of Fallot, ventricular or atrial septal defects, patent ductus arteriosus, truncus arteriosus, right ventricule hypoplasia.
  • systemic vascular system: coarctation of aorta, middle aortic syndrome, arterial hypoplasia (hepatic, renal, carotid, celiac), moyamoya disease, hypoplastic portal vein branch, intracranial bleeding.
  • vertebrae and skeleton: butterfly-like vertebrae, spina bifida, abnormal progression of interpedicular distances, shortening of distal phalanges and metacarpal bones, clinodactily.
  • eye : posterior embryotoxon, retinal pigmentation, iris strands, cataract, myopia, strabismus, glaucoma, optic disc drusen, fundus hypopigmentation, blindness.
  • kidney : mesangiolipidosis, tubular dysfunction, tubulointerstitial nephritis, renal hypoplasia, renal agenesis, horseshoe kidney, cysts.
  • ear : temporal bone abnormalities, chronic otitis media, deafness.
  • larynx : high pitched voice.
  • pancreas : diabetes, exocrine pancreatic insufficiency.
  • gut : small bowell atresia or stenosis.
  • lung : tracheal and bronchial stenosis.
  • face : prominent forehead, deep-set eyes, mild hypertelorism, straight nose, small pointed chin.
  • growth retardation.
  • mental retardation (?).
  • Neoplastic risk

    very rare hepatocellular carcinoma


    no specific treatment


    Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease (including liver transplantation), cardiac disease, and renal disease.



    3-7% of patients with Alagille syndrome have deletions of part or totality of the JAG1 gene in 20p and, in rare instances translocations : del(20p), del(20)(p11.2), del(20)(p12.3-p11.23), del(20)(p13-p12.2), ins(7;20), t(2;20)

    Genes involved and Proteins




    The gene spans 36 kb on the short arm of chromosome 20. It contains 26 exons (size from 28 bp to 2 kb) and 25 introns (size from 89 bp to nearly 9 kb).


    JAG1 is transcribed from centromere to telomere. The 26 exons are coding ; exon 1 is coding on the last 81 bases, and exon 26 on the first 455 bases. The transcript size is 5.5 kb.


    glycosylated transmembrane protein ; 1218 amino acids, predicted glycosylation sites: 960 ; 991 ; 1045 ; 1064.


    very wide; in heart, arteries, kidney, lung, pancreas, skeletal muscle, central nervous system, limb bud, etc. during embryonic and fetal development ; in adult tissues ; in tumors


    transmembrane plasma protein


    ligand of the Notch membrane receptors


  • serrate in D. melanogaster
  • lag-2 in C. elegans
  • jagged 1a and jagged 1b in zebrafish (D. rerio)
  • jagged2 ou serrateB in zebrafish (D. rerio)
  • X-serrate-1 in tadpole (Xenopus laevis)
  • C-serrate-1 and C-serrate-2 in chicken (Gallus gallus)
  • jagged1 and jagged2 in mouse (Mus musculus)
  • jagged1 and jagged2 in rat (Rattus norvegicus)
  • jagged1 and jagged2 in dog (Canis familiaris)
  • partial jagged1 in Bos taurus
  • JAGGED2 in Homo sapiens
  • Note

    95% of mutations are intragenic mutations located in the part of the JAG1 gene encoding extracellular and transmembrane domains of the protein. They are point mutations or small deletions\/insertions, leading to frame-shift mutations, premature stop codons, splice site mutations, and missense mutations.
    3-7% of mutations are deletions of part or totality of the JAG1 gene in 20p and, in rare instances translocations.
    Some AGS cases present with no mutation in the DNA of the 26 exons and exon boundaries of JAG1. In those instances, no prenatal diagnosis can be performed.
    Atlas Image
    Distribution of 344 intragenic JAG1 mutations in Alagille patients. We summarized all the mutations published so far and unpublished results from our laboratory and from A. Mantel (Hospital of Bicêtre). Seventy five per cent mutations (257\/344) are different at the DNA level. Sequencing exons 2, 4, 6, 9, 17, 23, and 24 which correspond to 35% of cDNA, detect 53% of all mutations.
    The signal peptide is encoded by exon 1, and the DSL domain by part of exon 4, the 16 EGF-like repeats correspond to exons 5-21, the cysteine-rich region partially overlaps exons 22-24, and the transmembrane domain and the intracellular region are encoded by exon 26.


    Mosaicism has been reported.

    To be noted


    http:\/\/\/ The Alagille syndrome alliancehttp:\/\/\/ Childrens liver association for support serviceshttp:\/\/ Verein Cholestase Erkrankter e.V.http:\/\/ Verein leberkrankes Kind e.V.


    Pubmed IDLast YearTitleAuthors
    38062901987Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.Alagille D et al
    20745581990Alagille syndrome and deletion of 20p.Anad F et al
    157728542005Expression of mutant JAGGED1 alleles in patients with Alagille syndrome.Boyer J et al
    111392472001Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome.Crosnier C et al
    80719711994Segregation analysis of Alagille syndrome.Dhorne-Pollet S et al
    111526642001Familial Tetralogy of Fallot caused by mutation in the jagged1 gene.Eldadah ZA et al
    113137612001Parental mosaicism of JAG1 mutations in families with Alagille syndrome.Giannakudis J et al
    100792561999Human ligands of the Notch receptor.Gray GE et al
    109783562000JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype.Jones EA et al
    157122722005Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients.Jurkiewicz D et al
    149931262004Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.Kamath BM et al
    158073122005Hepatocellular carcinoma occurring in alagille syndrome.Kim B et al
    95856031998Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.Krantz ID et al
    102130471999Jagged1 mutations in patients ascertained with isolated congenital heart defects.Krantz ID et al
    120220402002Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.Le Caignec C et al
    92077881997Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.Li L et al
    126498092003Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.Lu F et al
    125095722003Bleeding tendency in children with Alagille syndrome.Lykavieris P et al
    111578032001Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.Morrissette JD et al
    92077871997Mutations in the human Jagged1 gene are responsible for Alagille syndrome.Oda T et al
    124976402003Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.Röpke A et al
    111392392001Jagged1 mutations in alagille syndrome.Spinner NB et al
    47127761973Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease.Watson GH et al
    113594642001The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome.Yuan ZR et al