| Written | 2005-10 | Michèle Meunier-Rotival, Catherine Driancourt, Julie Boyer-Di Ponio |
| INSERM E0020 80 rue du General Leclerc, F-94276 Le Kremlin-Bicetre Cedex, France |
| Identity |
| Alias_names | AGS |
| JAGL1 | |
| Alagille syndrome | |
| Alias_symbol (synonym) | AHD |
| AWS | |
| HJ1 | |
| CD339 | |
| Other alias | JAGGED1 |
| hJ1 | |
| HGNC (Hugo) | JAG1 |
| LocusID (NCBI) | 182 |
| Atlas_Id | 41029 |
| Location | 20p12.2 [Link to chromosome band 20p12] |
| Location_base_pair | Starts at 10637684 and ends at 10674046 bp from pter ( according to hg19-Feb_2009) [Mapping JAG1.png] |
| Local_order | telomere PLCB1, PLCB4, PAK7, SNAP25, MKKS, JAG1 centromere |
| Fusion genes (updated 2016) | JAG1 (20p12.2) / HOOK3 (8p11.21) | JAG1 (20p12.2) / JAG1 (20p12.2) | SRRM2 (16p13.3) / JAG1 (20p12.2) |
| 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 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 | |
| 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 |
| Note | |
| 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. |
| Bibliography |
| 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 |
| 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, 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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. 2006;10(2):79-82. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/JAG1ID41029ch20p12.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
Breast: Ductal carcinoma
|
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Alagille syndrome (AGS) |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:09:40 CEST 2017 |
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