NOTCH2 mutations in Alagille syndrome.
BACKGROUND
Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.


METHODS
The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.


RESULTS
Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.


CONCLUSIONS
This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
Division of Gastroenterology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Canada.
Binita Maya
BM
Kamath
Robert C
RC
Bauer
Kathleen M
KM
Loomes
Grace
G
Chao
Jennifer
J
Gerfen
Anne
A
Hutchinson
Winita
W
Hardikar
Gideon
G
Hirschfield
Paloma
P
Jara
Ian D
ID
Krantz
Pablo
P
Lapunzina
Laura
L
Leonard
Simon
S
Ling
Vicky Lee
VL
Ng
Phuc Le
PL
Hoang
David A
DA
Piccoli
Nancy Bettina
NB
Spinner
D016738:Alagille Syndrome / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D019066:Facies; D015870:Gene Expression; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D010641:Phenotype; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D051883:Receptor, Notch2