Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   
X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

JAG1 jagged 1 (Alagille syndrome)

Identity

Other namesJAGGED1
HJ1
hJ1
JAGL1
HGNC (Hugo) JAG1
Location 20p12.1-11.23
Location_base_pair Starts at 10618332 and ends at 10654694 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order telomere PLCB1, PLCB4, PAK7, SNAP25, MKKS, JAG1 centromere

DNA/RNA

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

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.

Protein

 
  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).
Description glycosylated transmembrane protein ; 1218 amino acids,
predicted glycosylation sites : 960; 991; 1045; 1064.
Apparent size on Western blot : about 180 kDa.
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 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.
Homology
  • 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 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.
     
      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.
    Germinal Most mutations (70%) are de novo
    Somatic Cases of mosaicisms are described

    Implicated in

    Entity Alagille syndrome (AGS)
    Disease 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 Tetralogy of Fallot
    Disease The heterozygous mutation (G274D) in EGF2 of JAG1 has been reported in one family : affected family members also had characteristic facies.
      
    Entity Familial deafness, congenital heart defects, and posterior embryotoxon
    Disease The heterozygous mutation (C234Y) in EGF1 of JAG1 has been reported in one family.
      

    External links

    Nomenclature
    HGNC (Hugo)JAG1   6188
    Entrez_Gene (NCBI)JAG1  182  jagged 1 (Alagille syndrome)
    Cards
    AtlasJAG1ID41029ch20p12
    GeneCards (Weizmann)JAG1
    Ensembl (Hinxton)ENSG00000101384 [Gene_View]  JAG1 [Vega]
    AceView (NCBI)JAG1
    Genatlas (Paris)JAG1
    euGene (Indiana)182
    SOURCE (Stanford)NM_000214
    Gene Expression (Array Express) ENSG00000101384
    Genomic and cartography
    GoldenPath (UCSC)JAG1  -     chr20:10618332-10654694 -  20p12.1-p11.23   [Description]    (hg19-Feb_2009)
    EnsemblJAG1 - 20p12.1-p11.23 [CytoView]
    Mapping of homologs : NCBIJAG1 [Mapview]
    OMIM118450   187500   601920   
    Gene and transcription
    Gene : Genbank (Entrez)AF003837 AF028593 AI268246 AK302554 AK312722
    Reference sequence (RefSeq transcript) :SRSNM_000214
    Reference transcript : EntrezNM_000214
    RefSeq genomic : SRSAC_000063 AC_000152 NC_000020 NG_007496 NT_011387 NW_001838652 NW_927317
    RefSeq genomic : EntrezAC_000063 AC_000152 NC_000020 NG_007496 NT_011387 NW_001838652 NW_927317
    Consensus coding sequences : CCDS NCBIJAG1
    Cluster EST : UnigeneHs.720799 [ SRS ] Hs.720799 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)5669
    Protein : pattern, domain, 3D structure
    Protein : UniProt/SwissProtP78504 (SRS) P78504 (Expasy) P78504 (Uniprot)
    With graphics : InterProP78504
    Splice isoforms : VarSplice FASTAP78504(VarSplice FASTA)
    Domaine pattern : Prosite (SRS)ASX_HYDROXYL (PS00010)    DSL (PS51051)    EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    EGF_CA (PS01187)   
    Domain pattern : Prosite (Expaxy)ASX_HYDROXYL (PS00010)    DSL (PS51051)    EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    EGF_CA (PS01187)   
    Domains : Interpro (SRS)DSL    EGF    EGF-like    EGF-like_reg_CS    EGF-type_Asp/Asn_hydroxyl_site    EGF_2    EGF_3    EGF_Ca_bd    EGF_Ca_bd_2    EGF_Ca_bd_CS    EGF_extracell    Notch_ligand_N    VWF_C   
    Domains : Interpro (EBI)DSL    EGF    EGF-like    EGF-like_reg_CS    EGF-type_Asp/Asn_hydroxyl_site    EGF_2    EGF_3    EGF_Ca_bd    EGF_Ca_bd_2    EGF_Ca_bd_CS    EGF_extracell    Notch_ligand_N    VWF_C   
    Related proteins : CluSTrP78504
    Domain families : Pfam SRSDSL (PF01414)    EGF (PF00008)    EGF_2 (PF07974)    EGF_CA (PF07645)    MNNL (PF07657)   
    Domain families : Pfam SangerDSL (PF01414)    EGF (PF00008)    EGF_2 (PF07974)    EGF_CA (PF07645)    MNNL (PF07657)   
    Domain families : Pfam NCBIpfam01414    pfam00008    pfam07974    pfam07645    pfam07657   
    Domain families : Smart EMBLDSL (SM00051)  EGF (SM00181)  EGF_CA (SM00179)  VWC (SM00214)  
    Blocks (Seattle)P78504
    Crystal structure of protein : PDB SRS2KB9    2VJ2   
    Crystal structure of protein : PDBSum2KB9    2VJ2   
    Crystal structure of protein : IMB2KB9    2VJ2   
    Crystal structure of protein : PDB RSDB2KB9    2VJ2   
    Human Protein AtlasENSG00000101384
    HPRD03562
    Protein Interaction databases
    DIP (DOE-UCLA)P78504
    IntAct (EBI)P78504
    FunCoupENSG00000101384
    Polymorphism : SNP, mutations, diseases
    Single Nucleotide Polymorphism (SNP) : dbSNP NCBIJAG1
    SNP : GeneSNP UtahJAG1
    SNP : HGBaseJAG1
    Genetic variants : HAPMAPJAG1
    Somatic Mutations in Cancer : COSMICJAG1 
    Mutations and Diseases : HGMDJAG1
    Hereditary diseases : OMIM118450    187500    601920   
    Hereditary diseases : GENETests118450    187500    601920   
    Diseases : Genetic AssociationJAG1
    General knowledge
    Homologs : HomoloGeneJAG1
    Homology/Alignments : Family Browser UCSCJAG1
    Phylogenetic Trees/Animal Genes : TreeFamJAG1
    Chemical/Protein Interactions : CTD182
    Keywords Ontology : AmiGOangiogenesis  cell fate determination  morphogenesis of an epithelial sheet  Notch binding  structural molecule activity  calcium ion binding  protein binding  extracellular region  plasma membrane  integral to plasma membrane  cell communication  Notch signaling pathway  multicellular organismal development  nervous system development  growth factor activity  organ morphogenesis  membrane  hemopoiesis  keratinocyte differentiation  regulation of cell migration  regulation of cell proliferation  auditory receptor cell differentiation  myoblast differentiation  endothelial cell differentiation  negative regulation of cell differentiation  positive regulation of myeloid cell differentiation  positive regulation of Notch signaling pathway  inner ear development  
    Keywords Ontology : EGO-EBIangiogenesis  cell fate determination  morphogenesis of an epithelial sheet  Notch binding  structural molecule activity  calcium ion binding  protein binding  extracellular region  plasma membrane  integral to plasma membrane  cell communication  Notch signaling pathway  multicellular organismal development  nervous system development  growth factor activity  organ morphogenesis  membrane  hemopoiesis  keratinocyte differentiation  regulation of cell migration  regulation of cell proliferation  auditory receptor cell differentiation  myoblast differentiation  endothelial cell differentiation  negative regulation of cell differentiation  positive regulation of myeloid cell differentiation  positive regulation of Notch signaling pathway  inner ear development  
    Pathways : BIOCARTAPhosphoinositides and their downstream targets. [Genes]   
    Pathways : KEGGNotch signaling pathway
    Other databases
    Probes
    Probes : ImagenesJAG1 Related clones (RZPD - Berlin)
    Literature
    PubMed105 Pubmed reference(s) in Entrez
    PubGeneJAG1

    Bibliography

    Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.
    Alagille D, Estrada A, Hadchouel M, Gautier M, Odiˆ®vre 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
     
    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
     
    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 and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12.
    Oda T, Elkahloun AG, Meltzer PS, Chandrasekharappa SC
    Genomics. 1997 ; 43 (3) : 376-379.
    PMID 9268641
     
    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
     
    Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome.
    Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M
    Gastroenterology. 1999 ; 116 (5) : 1141-1148.
    PMID 10220506
     
    Alagille syndrome. The widening spectrum of arteriohepatic dysplasia.
    Crosnier C, Lykavieris P, Meunier-Rotival M, Hadchouel M
    Clinics in liver disease. 2000 ; 4 (4) : 765-778.
    PMID 11232356
     
    JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome.
    Crosnier C, Attiˆ©-Bitach T, Encha-Razavi F, Audollent S, Soudy F, Hadchouel M, Meunier-Rotival M, Vekemans M
    Hepatology (Baltimore, Md.). 2000 ; 32 (3) : 574-581.
    PMID 10960452
     
    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
     
    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
     
    The DNA sequence and comparative analysis of human chromosome 20.
    Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J
    Nature. 2001 ; 414 (6866) : 865-871.
    PMID 11780052
     
    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, Rˆpke 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
     
    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
     
    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
     
    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
     
    DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients.
    Heritage ML, MacMillan JC, Anderson GJ
    Human mutation. 2002 ; 20 (6) : page 481.
    PMID 12442286
     
    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
     
    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
     
    Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.
    Rˆpke A, Kujat A, Grˆ§ber M, Giannakudis J, Hansmann I
    Human mutation. 2003 ; 21 (1) : page 100.
    PMID 12497640
     
    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
     
    Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients.
    Jurkiewicz D, Popowska E, Glˆ§ser C, Hansmann I, Krajewska-Walasek M
    Human mutation. 2005 ; 25 (3) : page 321.
    PMID 15712272
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

    Contributor(s)

    Written10-2005Michèle Meunier-Rotival, Catherine Driancourt, Julie Boyer-Di Ponio

    Citation

    This paper should be referenced as such :
    Meunier-Rotival M, Driancourt C, Boyer-Di Ponio J . JAG1 jagged 1 (Alagille syndrome). Atlas Genet Cytogenet Oncol Haematol. October 2005 .
    URL : http://AtlasGeneticsOncology.org/Genes/JAG1ID41029ch20p12.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Jul 15 14:42:02 CEST 2010
    Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us

    jlhuret@AtlasGeneticsOncology.org.