JAG1

Identity

Other names	JAGGED1
	HJ1
	hJ1
	JAGL1
Hugo	JAG1
Location	20p12.1-11.23
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
Hugo	JAG1
GDB	JAG1
Entrez_Gene	JAG1  182  jagged 1 (Alagille syndrome)
	Cards
Atlas	JAG1ID41029ch20p12
GeneCards	JAG1
Ensembl	JAG1 [Search_View]   ENSG00000101384 [Gene_View]
Genatlas	JAG1
GeneLynx	JAG1
eGenome	JAG1
euGene	182
	Genomic and cartography
GoldenPath	JAG1  -     chr20:10566334-10602590 -  20p12.1-p11.23   [Description]    (hg18-Mar_2006)
Ensembl	JAG1 - 20p12.1-p11.23 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	JAG1
	Gene and transcription
Genbank	AF003837 [ ENTREZ ]
Genbank	AF028593 [ ENTREZ ]
Genbank	BC098393 [ ENTREZ ]
Genbank	BC126205 [ ENTREZ ]
Genbank	BC126207 [ ENTREZ ]
RefSeq	NM_000214 [ SRS ]    NM_000214 [ ENTREZ ]
RefSeq	AC_000063 [ SRS ]    AC_000063 [ ENTREZ ]
RefSeq	NC_000020 [ SRS ]    NC_000020 [ ENTREZ ]
RefSeq	NT_011387 [ SRS ]    NT_011387 [ ENTREZ ]
RefSeq	NW_927317 [ SRS ]    NW_927317 [ ENTREZ ]
AceView	JAG1 AceView - NCBI
Unigene	Hs.224012 [ SRS ]    Hs.224012 [ NCBI ]     HS224012 [ spliceNest ]
Fast-db	5669 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P78504 [ SRS]    P78504 [ EXPASY ]     P78504 [ INTERPRO ]
Prosite	PS00010 ASX_HYDROXYL [ SRS ]    PS00010 ASX_HYDROXYL [ Expasy ]
Prosite	PS51051 DSL [ SRS ]    PS51051 DSL [ Expasy ]
Prosite	PS00022 EGF_1 [ SRS ]    PS00022 EGF_1 [ Expasy ]
Prosite	PS01186 EGF_2 [ SRS ]    PS01186 EGF_2 [ Expasy ]
Prosite	PS50026 EGF_3 [ SRS ]    PS50026 EGF_3 [ Expasy ]
Prosite	PS01187 EGF_CA [ SRS ]    PS01187 EGF_CA [ Expasy ]
Interpro	IPR000152 Asx_hydroxyl_S [ SRS ]    IPR000152 Asx_hydroxyl_S [ EBI ]
Interpro	IPR001774 DSL [ SRS ]    IPR001774 DSL [ EBI ]
Interpro	IPR006210 EGF [ SRS ]    IPR006210 EGF [ EBI ]
Interpro	IPR001438 EGF_2 [ SRS ]    IPR001438 EGF_2 [ EBI ]
Interpro	IPR000742 EGF_3 [ SRS ]    IPR000742 EGF_3 [ EBI ]
Interpro	IPR001881 EGF_Ca_bd [ SRS ]    IPR001881 EGF_Ca_bd [ EBI ]
Interpro	IPR006209 EGF_like [ SRS ]    IPR006209 EGF_like [ EBI ]
Interpro	IPR013032 EGF_like_reg_CS [ SRS ]    IPR013032 EGF_like_reg_CS [ EBI ]
Interpro	IPR011651 Notch_ligand_N [ SRS ]    IPR011651 Notch_ligand_N [ EBI ]
Interpro	IPR001007 VWF_C [ SRS ]    IPR001007 VWF_C [ EBI ]
CluSTr	P78504
Pfam	PF01414 DSL [ SRS ]    PF01414 DSL [ Sanger ]    pfam01414 [ NCBI-CDD ]
Pfam	PF00008 EGF [ SRS ]    PF00008 EGF [ Sanger ]    pfam00008 [ NCBI-CDD ]
Pfam	PF07657 MNNL [ SRS ]    PF07657 MNNL [ Sanger ]    pfam07657 [ NCBI-CDD ]
Smart	SM00051 DSL [EMBL]
Smart	SM00181 EGF [EMBL]
Smart	SM00179 EGF_CA [EMBL]
Smart	SM00214 VWC [EMBL]
Blocks	P78504
HPRD	03562
	Protein Interaction databases
DIP	P78504
IntAct	P78504
	Polymorphism : SNP, mutations, diseases
OMIM	118450;187500;601920    [ map ]
GENECLINICS	118450;187500;601920
SNP	JAG1 [dbSNP-NCBI]
SNP	NM_000214 [SNP-NCI]
SNP	JAG1 [GeneSNPs - Utah]  JAG1] [HGBASE - SRS]
HAPMAP	JAG1 [HAPMAP]
COSMIC	JAG1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	JAG1
	General knowledge
Family Browser	JAG1 [UCSC Family Browser]
SOURCE	NM_000214
SMD	Hs.224012
SAGE	Hs.224012
GO	angiogenesis [Amigo]  angiogenesis
GO	cell fate determination [Amigo]  cell fate determination
GO	morphogenesis of an epithelial sheet [Amigo]  morphogenesis of an epithelial sheet
GO	Notch binding [Amigo]  Notch binding
GO	structural molecule activity [Amigo]  structural molecule activity
GO	calcium ion binding [Amigo]  calcium ion binding
GO	calcium ion binding [Amigo]  calcium ion binding
GO	protein binding [Amigo]  protein binding
GO	extracellular region [Amigo]  extracellular region
GO	plasma membrane [Amigo]  plasma membrane
GO	integral to plasma membrane [Amigo]  integral to plasma membrane
GO	cell communication [Amigo]  cell communication
GO	Notch signaling pathway [Amigo]  Notch signaling pathway
GO	multicellular organismal development [Amigo]  multicellular organismal development
GO	nervous system development [Amigo]  nervous system development
GO	growth factor activity [Amigo]  growth factor activity
GO	organ morphogenesis [Amigo]  organ morphogenesis
GO	hemopoiesis [Amigo]  hemopoiesis
GO	keratinocyte differentiation [Amigo]  keratinocyte differentiation
GO	regulation of cell migration [Amigo]  regulation of cell migration
GO	regulation of cell proliferation [Amigo]  regulation of cell proliferation
GO	auditory receptor cell differentiation [Amigo]  auditory receptor cell differentiation
GO	myoblast differentiation [Amigo]  myoblast differentiation
GO	endothelial cell differentiation [Amigo]  endothelial cell differentiation
GO	negative regulation of cell differentiation [Amigo]  negative regulation of cell differentiation
GO	positive regulation of myeloid cell differentiation [Amigo]  positive regulation of myeloid cell differentiation
GO	positive regulation of Notch signaling pathway [Amigo]  positive regulation of Notch signaling pathway
GO	inner ear development [Amigo]  inner ear development
KEGG	Notch signaling pathway
PubGene	JAG1
TreeFam	JAG1
CTD	182 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	JAG1 Related clones (RZPD - Berlin)
	PubMed
PubMed	71 Pubmed reference(s) in LocusLink

Bibliography

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PMID 3806290

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PMID 2074558

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Mutations in the human Jagged1 gene are responsible for Alagille syndrome.

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Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome.

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JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome.

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PMID 10960452

JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype.

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PMID 10978356

Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome.

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Human mutation. 2001 ; 17 (1) : 72-73.

PMID 11139247

The DNA sequence and comparative analysis of human chromosome 20.

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PMID 11780052

Familial Tetralogy of Fallot caused by mutation in the jagged1 gene.

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Human molecular genetics. 2001 ; 10 (2) : 163-169.

PMID 11152664

Parental mosaicism of JAG1 mutations in families with Alagille syndrome.

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PMID 11313761

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PMID 11157803

Jagged1 mutations in alagille syndrome.

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PMID 11139239

The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome.

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PMID 11359464

DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients.

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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.

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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.

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American journal of human genetics. 2003 ; 72 (4) : 1065-1070.

PMID 12649809

Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome.

Rˆ�pke 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.

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Human genetics. 2005 ; 116 (6) : 445-453.

PMID 15772854

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Human mutation. 2005 ; 25 (3) : page 321.

PMID 15712272

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Contributor(s)

Written	10-2005	Michèle 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. 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 : Wed Jul 2 08:24:21 2008