Alagille syndrome (AGS)

Identity

Other names	Alagille-Watson syndrome (AWS)
	Arteriohepatic dysplasia (AHD)
	Cholestasis with peripheral pulmonary stenosis
	Hepatic ductular paucity, syndromatic
Atlas_Id	10090
Genes implicated in	JAG1  NOTCH2
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.

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)

Other findings

Note	There is no phenotype-genotype correlation

Genes involved and Proteins

Gene Name	JAG1
Alias	JAGGED1
Location	20p12.1-11.23

DNA/RNA
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.

Protein
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

Mutations
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.
Somatic	Mosaicism has been reported.

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

Segregation analysis of Alagille syndrome.

Dhorne-Pollet S, Deleuze JF, Hadchouel M, Bonaïti-Pellié C

Journal of medical genetics. 1994 ; 31 (6) : 453-457.

PMID 8071971

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

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PMID 11313761

Human ligands of the Notch receptor.

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The American journal of pathology. 1999 ; 154 (3) : 785-794.

PMID 10079256

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

Jones EA, Clement-Jones M, Wilson DI

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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

Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.

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PMID 14993126

Hepatocellular carcinoma occurring in alagille syndrome.

Kim B, Park SH, Yang HR, Seo JK, Kim WS, Chi JG

Pathology, research and practice. 2005 ; 201 (1) : 55-60.

PMID 15807312

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

Jagged1 mutations in patients ascertained with isolated congenital heart defects.

Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, Goldmuntz E, Spinner NB

American journal of medical genetics. 1999 ; 84 (1) : 56-60.

PMID 10213047

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

Bleeding tendency in children with Alagille syndrome.

Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M

Pediatrics. 2003 ; 111 (1) : 167-170.

PMID 12509572

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

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 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

Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease.

Watson GH, Miller V

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PMID 4712776

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 ; Hadchouel, M

Alagille syndrome (AGS)

Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):131-133.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/AlagilleID10090.html

External links

OMIM	118450
OMIM	610205
Orphanet	Alagille syndrome
MeSH	D016738
MedGen	D016738
UMLS	C0085280
ICD-10	Q44.7
Association	The Alagille syndrome alliance
Association	Children's liver association for support services
Association	Verein Cholestase Erkrankter e.V.
Association	Verein leberkrankes Kind e.V.

REVIEW articles	automatic search in PubMed
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