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Alagille syndrome (AGS)

Written2005-10Michçle Meunier-Rotival, Michelle Hadchouel
INSERM E0020 80 rue du General Leclerc, F-94276 Le Kremlin-Bicetre Cedex, France

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Other namesAlagille-Watson syndrome (AWS)
Arteriohepatic dysplasia (AHD)
Cholestasis with peripheral pulmonary stenosis
Hepatic ductular paucity, syndromatic
Atlas_Id 10090
Genes implicated inJAG1  NOTCH2  
Note 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
Inheritance 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.


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
    Treatment no specific treatment
    Prognosis Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease (including liver transplantation), cardiac disease, and renal disease.


    Note 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)

    Other findings

    Note There is no phenotype-genotype correlation

    Genes involved and Proteins

    Gene NameJAG1
    Alias JAGGED1
    Location 20p12.1-11.23
    Description 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).
    Transcription 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.
    Description glycosylated transmembrane protein ; 1218 amino acids, predicted glycosylation sites: 960 ; 991 ; 1045 ; 1064.
    Expression 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
    Localisation transmembrane plasma protein
    Function 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
  • Mutations
    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.
    Somatic Mosaicism has been reported.


    Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.
    Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP
    The Journal of pediatrics. 1987 ; 110 (2) : 195-200.
    PMID 3806290
    Alagille syndrome and deletion of 20p.
    Anad F, Burn J, Matthews D, Cross I, Davison BC, Mueller R, Sands M, Lillington DM, Eastham E
    Journal of medical genetics. 1990 ; 27 (12) : 729-737.
    PMID 2074558
    Expression of mutant JAGGED1 alleles in patients with Alagille syndrome.
    Boyer J, Crosnier C, Driancourt C, Raynaud N, Gonzales M, Hadchouel M, Meunier-Rotival M
    Human genetics. 2005 ; 116 (6) : 445-453.
    PMID 15772854
    Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome.
    Crosnier C, Driancourt C, Raynaud N, Hadchouel M, Meunier-Rotival M
    Human mutation. 2001 ; 17 (1) : 72-73.
    PMID 11139247
    Segregation analysis of Alagille syndrome.
    Dhorne-Pollet S, Deleuze JF, Hadchouel M, Bonaïti-Pellié C
    Journal of medical genetics. 1994 ; 31 (6) : 453-457.
    PMID 8071971
    Familial Tetralogy of Fallot caused by mutation in the jagged1 gene.
    Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC
    Human molecular genetics. 2001 ; 10 (2) : 163-169.
    PMID 11152664
    Parental mosaicism of JAG1 mutations in families with Alagille syndrome.
    Giannakudis J, Röpke A, Kujat A, Krajewska-Walasek M, Hughes H, Fryns JP, Bankier A, Amor D, Schlicker M, Hansmann I
    European journal of human genetics : EJHG. 2001 ; 9 (3) : 209-216.
    PMID 11313761
    Human ligands of the Notch receptor.
    Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S
    The American journal of pathology. 1999 ; 154 (3) : 785-794.
    PMID 10079256
    JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype.
    Jones EA, Clement-Jones M, Wilson DI
    Journal of medical genetics. 2000 ; 37 (9) : 658-662.
    PMID 10978356
    Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients.
    Jurkiewicz D, Popowska E, Gläser C, Hansmann I, Krajewska-Walasek M
    Human mutation. 2005 ; 25 (3) : page 321.
    PMID 15712272
    Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.
    Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID
    Circulation. 2004 ; 109 (11) : 1354-1358.
    PMID 14993126
    Hepatocellular carcinoma occurring in alagille syndrome.
    Kim B, Park SH, Yang HR, Seo JK, Kim WS, Chi JG
    Pathology, research and practice. 2005 ; 201 (1) : 55-60.
    PMID 15807312
    Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.
    Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB
    American journal of human genetics. 1998 ; 62 (6) : 1361-1369.
    PMID 9585603
    Jagged1 mutations in patients ascertained with isolated congenital heart defects.
    Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, Goldmuntz E, Spinner NB
    American journal of medical genetics. 1999 ; 84 (1) : 56-60.
    PMID 10213047
    Familial 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, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, Moisan JP
    American journal of human genetics. 2002 ; 71 (1) : 180-186.
    PMID 12022040
    Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.
    Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB
    Nature genetics. 1997 ; 16 (3) : 243-251.
    PMID 9207788
    Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage.
    Lu F, Morrissette JJ, Spinner NB
    American journal of human genetics. 2003 ; 72 (4) : 1065-1070.
    PMID 12649809
    Bleeding tendency in children with Alagille syndrome.
    Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M
    Pediatrics. 2003 ; 111 (1) : 167-170.
    PMID 12509572
    Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.
    Morrissette JD, Colliton RP, Spinner NB
    Human molecular genetics. 2001 ; 10 (4) : 405-413.
    PMID 11157803
    Mutations in the human Jagged1 gene are responsible for Alagille syndrome.
    Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC
    Nature genetics. 1997 ; 16 (3) : 235-242.
    PMID 9207787
    Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.
    Röpke A, Kujat A, Gräber M, Giannakudis J, Hansmann I
    Human mutation. 2003 ; 21 (1) : page 100.
    PMID 12497640
    Jagged1 mutations in alagille syndrome.
    Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M
    Human mutation. 2001 ; 17 (1) : 18-33.
    PMID 11139239
    Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease.
    Watson GH, Miller V
    Archives of disease in childhood. 1973 ; 48 (6) : 459-466.
    PMID 4712776
    The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome.
    Yuan ZR, Okaniwa M, Nagata I, Tazawa Y, Ito M, Kawarazaki H, Inomata Y, Okano S, Yoshida T, Kobayashi N, Kohsaka T
    Clinical genetics. 2001 ; 59 (5) : 330-337.
    PMID 11359464


    This paper should be referenced as such :
    Meunier-Rotival, M ; Hadchouel, M
    Alagille syndrome (AGS)
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):131-133.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    External links

    OrphanetAlagille syndrome
    AssociationThe Alagille syndrome alliance
    AssociationChildren's liver association for support services
    AssociationVerein Cholestase Erkrankter e.V.
    AssociationVerein leberkrankes Kind e.V.
    REVIEW articlesautomatic search in PubMed
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    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Tue Sep 27 16:11:47 CEST 2016

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