Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Jul;79(1):169-73.
doi: 10.1086/505332. Epub 2006 May 10.

NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway

Ryan McDaniell  1 , Daniel M Warthen, Pedro A Sanchez-Lara, Athma Pai, Ian D Krantz, David A Piccoli, Nancy B Spinner
Affiliations

NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway

Ryan McDaniell et al. Am J Hum Genet. 2006 Jul.

Abstract

Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
NOTCH2 mutation in family 1. a, Proband and his mother demonstrate features of AGS. Family members marked with an asterisk (*) were tested for the presence of the mutation but had only wild-type sequence. Individuals marked with a section symbol (§) had mutant sequences. b, Genomic DNA (gDNA) and cDNA sequencing demonstrates the presence and consequences of a mutation in the splice site of exon 33 in the proband and his mother. c, cDNA amplification and electrophoresis demonstrate the abnormally spliced product (arrow). d, Predicted protein product is represented below the diagram of the wild-type Notch2 protein (mutation marked by an asterisk). EGFR = EGF-like repeats.
Figure 2.
Figure 2.
NOTCH2 mutation in family 2. a, Proband, her mother, and her grandmother had clinical features associated with AGS. The family member marked with an asterisk (*) was tested for the presence of the mutation but had only wild-type sequence. Individuals marked with a section symbol (§) had mutant sequences. b, Sequence analysis shows a mutation in exon 8 in all three affected individuals. c, The mutation (asterisk) is predicted to cause substitution of a tyrosine for a cysteine residue in EGF-like repeat 11 of Notch2.
See this image and copyright information in PMC

Similar articles

  • NOTCH2 mutations in Alagille syndrome.
    Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli DA, Spinner NB. Kamath BM, et al. J Med Genet. 2012 Feb;49(2):138-44. doi: 10.1136/jmedgenet-2011-100544. Epub 2011 Dec 29. J Med Genet. 2012. PMID: 22209762 Free PMC article.
  • Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.
    Andersson ER, Chivukula IV, Hankeova S, Sjöqvist M, Tsoi YL, Ramsköld D, Masek J, Elmansuri A, Hoogendoorn A, Vazquez E, Storvall H, Netušilová J, Huch M, Fischler B, Ellis E, Contreras A, Nemeth A, Chien KC, Clevers H, Sandberg R, Bryja V, Lendahl U. Andersson ER, et al. Gastroenterology. 2018 Mar;154(4):1080-1095. doi: 10.1053/j.gastro.2017.11.002. Epub 2017 Nov 21. Gastroenterology. 2018. PMID: 29162437 Free PMC article.
  • Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification.
    Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, Nassur JA, Rand EB, Krock BL, Kamath BM, Krantz ID, Piccoli DA, Loomes KM, Spinner NB. Gilbert MA, et al. Hum Mutat. 2019 Dec;40(12):2197-2220. doi: 10.1002/humu.23879. Epub 2019 Aug 26. Hum Mutat. 2019. PMID: 31343788 Free PMC article.
  • Renal involvement and the role of Notch signalling in Alagille syndrome.
    Kamath BM, Spinner NB, Rosenblum ND. Kamath BM, et al. Nat Rev Nephrol. 2013 Jul;9(7):409-18. doi: 10.1038/nrneph.2013.102. Epub 2013 Jun 11. Nat Rev Nephrol. 2013. PMID: 23752887 Review.
  • Alagille Syndrome.
    Mitchell E, Gilbert M, Loomes KM. Mitchell E, et al. Clin Liver Dis. 2018 Nov;22(4):625-641. doi: 10.1016/j.cld.2018.06.001. Epub 2018 Aug 22. Clin Liver Dis. 2018. PMID: 30266153 Review.
See all similar articles

Cited by

See all "Cited by" articles

References

Web Resources

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for NOTCH2 cDNA [accession number NM_024408.2])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AGS) - PubMed

References

    1. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP (1987) Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110:195–20010.1016/S0022-3476(87)80153-1 - DOI - PubMed
    1. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA (1999) Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29:822–82910.1002/hep.510290331 - DOI - PubMed
    1. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont MEM, Rand EB, Piccoli DA, Hood L, Spinner NB (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243–25110.1038/ng0797-243 - DOI - PubMed
    1. Oda T, Elkahlous AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PM, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16:235–24210.1038/ng0797-235 - DOI - PubMed
    1. Gridley T (2003) Notch signaling and inherited disease syndromes. Hum Mol Genet Review Issue 1 12:R9–R1310.1093/hmg/ddg052 - DOI - PubMed

Publication types

Substances