Alagille syndrome (AGS)

2005-10-01 Michçle Meunier-Rotival , Michelle Hadchouel Affiliation

Identity

Name

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

liver : jaundice, pruritus, xanthomas, bile duct paucity, biochemical cholestasis and hypercholesterolemia. Liver transplantation is performed in about 25% cases.

cardiovascular system : peripheral pulmonary stenosis, coarctation of aorta, tetralogy of Fallot, ventricular or atrial septal defects, patent ductus arteriosus, truncus arteriosus, right ventricule hypoplasia.

systemic vascular system: coarctation of aorta, middle aortic syndrome, arterial hypoplasia (hepatic, renal, carotid, celiac), moyamoya disease, hypoplastic portal vein branch, intracranial bleeding.

vertebrae and skeleton: butterfly-like vertebrae, spina bifida, abnormal progression of interpedicular distances, shortening of distal phalanges and metacarpal bones, clinodactily.

eye : posterior embryotoxon, retinal pigmentation, iris strands, cataract, myopia, strabismus, glaucoma, optic disc drusen, fundus hypopigmentation, blindness.

kidney : mesangiolipidosis, tubular dysfunction, tubulointerstitial nephritis, renal hypoplasia, renal agenesis, horseshoe kidney, cysts.

ear : temporal bone abnormalities, chronic otitis media, deafness.

larynx : high pitched voice.

pancreas : diabetes, exocrine pancreatic insufficiency.

gut : small bowell atresia or stenosis.

lung : tracheal and bronchial stenosis.

face : prominent forehead, deep-set eyes, mild hypertelorism, straight nose, small pointed chin.

growth retardation.

mental retardation (?).

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

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

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.

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.

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