Identity
Name
Alagille syndrome (AGS)
Alias
Alagille-Watson syndrome (AWS) , Arteriohepatic dysplasia (AHD) , Cholestasis with peripheral pulmonary stenosis , Hepatic ductular paucity, syndromatic
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.
Omim
118450 , 610205
Mesh
D016738
Orphanet
52 Alagille syndrome
Umls
C0085280
Clinics
Phenotype and clinics
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.
Cytogenetics
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)
Genes involved and Proteins
Alias
JAGGED1
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
Homology
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.
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.
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 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.
Somatic
Mosaicism has been reported.
To be noted
Associations
http:\/\/www.alagille.org\/ The Alagille syndrome alliancehttp:\/\/www.classkids.org\/ Childrens liver association for support serviceshttp:\/\/www.cholestase-verein.de Verein Cholestase Erkrankter e.V.http:\/\/www.leberkrankes-kind.de Verein leberkrankes Kind e.V.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 3806290 | 1987 | Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. | Alagille D et al |
| 2074558 | 1990 | Alagille syndrome and deletion of 20p. | Anad F et al |
| 15772854 | 2005 | Expression of mutant JAGGED1 alleles in patients with Alagille syndrome. | Boyer J et al |
| 11139247 | 2001 | Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. | Crosnier C et al |
| 8071971 | 1994 | Segregation analysis of Alagille syndrome. | Dhorne-Pollet S et al |
| 11152664 | 2001 | Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. | Eldadah ZA et al |
| 11313761 | 2001 | Parental mosaicism of JAG1 mutations in families with Alagille syndrome. | Giannakudis J et al |
| 10079256 | 1999 | Human ligands of the Notch receptor. | Gray GE et al |
| 10978356 | 2000 | JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. | Jones EA et al |
| 15712272 | 2005 | Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients. | Jurkiewicz D et al |
| 14993126 | 2004 | Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. | Kamath BM et al |
| 15807312 | 2005 | Hepatocellular carcinoma occurring in alagille syndrome. | Kim B et al |
| 9585603 | 1998 | Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. | Krantz ID et al |
| 10213047 | 1999 | Jagged1 mutations in patients ascertained with isolated congenital heart defects. | Krantz ID et al |
| 12022040 | 2002 | 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 et al |
| 9207788 | 1997 | Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. | Li L et al |
| 12649809 | 2003 | Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage. | Lu F et al |
| 12509572 | 2003 | Bleeding tendency in children with Alagille syndrome. | Lykavieris P et al |
| 11157803 | 2001 | Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. | Morrissette JD et al |
| 9207787 | 1997 | Mutations in the human Jagged1 gene are responsible for Alagille syndrome. | Oda T et al |
| 12497640 | 2003 | Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. | Röpke A et al |
| 11139239 | 2001 | Jagged1 mutations in alagille syndrome. | Spinner NB et al |
| 4712776 | 1973 | Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. | Watson GH et al |
| 11359464 | 2001 | The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome. | Yuan ZR et al |
External Links
Citation
Michçle Meunier-Rotival ; Michelle Hadchouel
Alagille syndrome (AGS)
Atlas Genet Cytogenet Oncol Haematol. 2005-10-01
Online version: http://atlasgeneticsoncology.org/cancer-prone-disease/10090/alagille-syndrome-(ags)
