JAG1 jagged 1 (Alagille syndrome)

2005-10-01   Michèle Meunier-Rotival , Catherine Driancourt , Julie Boyer-Di Ponio 

INSERM E0020 80 rue du General Leclerc, F-94276 Le Kremlin-Bicetre Cedex, France




Atlas Image
Table 1. Polymorphisms in the cDNA of JAG1. GenBank Accession no : HSU73936.


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) : table 1. Intron 19 contains a CA dinucleotide repeat which is a highly polymorphic marker : D20S1154 (12 alleles with heterozygosity of 85.8% and PIC of 0.844).

Size of exons and introns of the human JAG1 gene
exon 1 : 494; intron 1 : 443; exon 2 : 306; intron 2 : 8686; exon 3 : 52; intron 3 : 5240; exon 4 : 255; intron 4 : 2009; exon 5 : 61; intron 5 : 3799; exon 6 : 131; intron 6 : 217; exon 7 : 120; intron 7 : 436; exon 8 : 114; intron 8 : 1220; exon 9 : 114; intron 9 : 611; exon 10 : 114; intron 10: 414; exon 11 : 47; intron 11 : 338; exon 12 : 174; intron 12 : 438; exon 13 : 151; intron 13 : 856; exon 14 : 165; intron 14 : 854; exon 15 : 114; intron 15 : 501; exon 16 : 114; intron 16 99; exon 17 : 114; intron 17 : 163; exon 18 : 117; intron 18 : 478; exon 19 : 28; intron 19 : 493; exon 20 : 86; intron 20 : 1176; exon 21 : 114; intron 21 : 595; exon 22 : 110; intron 22 : 89; exon 23 : 234; intron 23 : 215; exon 24 : 132; intron 24 : 179; exon 25 : 151; intron 25 : 827; exon 26 : 1979

Polymorphisms were described in the cDNA sequence (table 1).


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.


Atlas Image
Figure 1. Schematic representation of the JAG1 protein (1218 amino acids). It contains signal peptide : SP (1-33), delta, serrate, lag-2 domain : DSL (185-229), 16 EGF-like repeats (230-856 ; cf table 3), cysteine-rich region : CR (863-1002), transmembrane domain : TM (1068-1093), intracellular (cytoplasmic) part : IC (1094-1218).
Table 2. EGF-like repeats of the human JAG1 protein. A : the 16 EGF motifs are aligned. A 24-amino acid insertion is present in EGF10 (in grey, as in human JAG2 protein). The numbers above the sequences refer to cysteine residues (C in blue). Each EGF-like repeat contains 6 cysteine residues, able to make disulfide bond bridges : 1st with 3th ; 2nd with 4th and 5th with 6th. Some of these repeats are calcium-binding EGF-like domains, which have at their amino-terminus, negatively charged or polar residues such as aspartic acid (D), glutamic acid (E), glutamine (Q), and asparagine (N). B : consensus sequence of an EGF-like repeat. x is any amino acid. Three glycine (G) residues are conserved (in green). The amino acid Z (in yellow) could be either phenylalanine (F), tryptophan (W), tyrosine (Y) or histidine (H).


glycosylated transmembrane protein ; 1218 amino acids,
predicted glycosylation sites : 960; 991; 1045; 1064.
Apparent size on Western blot : about 180 kDa.


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 family of receptors. The Notch signaling pathway plays a crucial role during embryonic pattern formation, controls many conserved cell determination events and defines a fundamental mechanism controlling cell fate. It is involved in lineage cell decisions in a variety of tissues. It plays a role in hematopoiesis, vascular development and angiogenesis, myogenesis, neurogenesis, somitogenesis ; kidney, eye, ear, and tooth development etc.


  • 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


    Heterozygous mutations in JAG1 gene cause Alagille syndrome.
    Five per cent are deletions on the short arm of chromosome 20 that could be visible in cytogenetics : the whole gene or part of the gene, or a region larger than the gene can be deleted. : del(20p), del(20)(p11.2), del(20)(p12.3-p11.23), del(20)(p13-p12.2), ins(7;20), t(2;20).
    Ninety five per cent are point intragenic mutations that are spread over the entire gene, with the exception of the part of the gene encoding the intracellular part of the protein (see the structure of the protein in Figure 2). Seventy per cent of mutations are nonsense or frameshift mutations leading to premature stop codons ; 15% are missense mutations and 14% are splice site mutations (Figure 3). The most frequent mutation ( "delCAGT" in exon 17) accounts for 5% of all mutations.
    Some AGS probands 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
    Figure 3. 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 Kremlin-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.


    Most mutations (70%) are de novo


    Cases of mosaicisms are described

    Implicated in

    Entity name
    Alagille syndrome (AGS)
    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. AGS presents with a highly variable expressivity and nearly complete penetrance.
    Entity name
    Tetralogy of Fallot
    The heterozygous mutation (G274D) in EGF2 of JAG1 has been reported in one family : affected family members also had characteristic facies.
    Entity name
    Familial deafness, congenital heart defects, and posterior embryotoxon
    The heterozygous mutation (C234Y) in EGF1 of JAG1 has been reported in one family.


    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
    117800522001The DNA sequence and comparative analysis of human chromosome 20.Deloukas P 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
    124422862002DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients.Heritage ML 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
    95856031998Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.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
    111578032001Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome.Morrissette JD et al
    92686411997Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12.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
    113594642001The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome.Yuan ZR et al

    Other Information

    Locus ID:

    NCBI: 182
    MIM: 601920
    HGNC: 6188
    Ensembl: ENSG00000101384


    dbSNP: 182
    ClinVar: 182
    TCGA: ENSG00000101384


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Notch signaling pathwayKEGGko04330
    Notch signaling pathwayKEGGhsa04330
    TNF signaling pathwayKEGGhsa04668
    TNF signaling pathwayKEGGko04668
    Diseases of signal transductionREACTOMER-HSA-5663202
    Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
    Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation MutantREACTOMER-HSA-2660825
    Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation MutantREACTOMER-HSA-2660826
    Signaling by NOTCH1 HD Domain Mutants in CancerREACTOMER-HSA-2691230
    Constitutive Signaling by NOTCH1 HD Domain MutantsREACTOMER-HSA-2691232
    Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
    Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
    Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
    Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
    Signal TransductionREACTOMER-HSA-162582
    Signaling by NOTCHREACTOMER-HSA-157118
    Signaling by NOTCH1REACTOMER-HSA-1980143
    Activated NOTCH1 Transmits Signal to the NucleusREACTOMER-HSA-2122948
    Signaling by NOTCH2REACTOMER-HSA-1980145
    NOTCH2 Activation and Transmission of Signal to the NucleusREACTOMER-HSA-2979096
    Signaling by NOTCH3REACTOMER-HSA-1980148
    Signaling by NOTCH4REACTOMER-HSA-1980150
    Endocrine resistanceKEGGko01522
    Endocrine resistanceKEGGhsa01522
    Breast cancerKEGGko05224
    Breast cancerKEGGhsa05224
    Th1 and Th2 cell differentiationKEGGko04658
    Th1 and Th2 cell differentiationKEGGhsa04658
    Apelin signaling pathwayKEGGhsa04371

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    180600362007IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.290
    194304822009Multiple loci associated with indices of renal function and chronic kidney disease.245
    157816502005Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.190
    179843062007Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin.173
    233756362013Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1.155
    123572472002Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation.140
    154661722004JAGGED1 expression is associated with prostate cancer metastasis and recurrence.132
    191508862009NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1.117
    193987212009MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation.108
    128266752003The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments.102


    Michèle Meunier-Rotival ; Catherine Driancourt ; Julie Boyer-Di Ponio

    JAG1 jagged 1 (Alagille syndrome)

    Atlas Genet Cytogenet Oncol Haematol. 2005-10-01

    Online version: http://atlasgeneticsoncology.org/gene/41029/jag1-jagged-1-(alagille-syndrome)