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Mutations in the human Jagged1 gene are responsible for Alagille syndrome

Nature Genetics volume 16, pages 235–242 (1997)Cite this article

Abstract

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene to 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon–intron structure of JAG1 allowed detailed mutational analysis of DMA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.

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References

  1. Alagille, D., Odievre, M., Gautier, M., Dommergues, J.P. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J. Pediatr. 86, 63–71 (1975).

    Article  CAS  Google Scholar 

  2. Alagille, D. et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J. Pediatr. 110, 195–200 (1987).

    Article  CAS  Google Scholar 

  3. Danks, D.M., Campbell, P.E., Jack, I., Rogers, J. & Smith, A.L. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch. Dis. Child 52, 360–367 (1977).

    Article  CAS  Google Scholar 

  4. Dhorne-Pollet, S., Deleuze, J.F., Hadchouel, M. & Bonaiti-Pellie, C. Segregation analysis of Alagille syndrome. J. Med. Genet 31, 453–457 (1994).

    Article  CAS  Google Scholar 

  5. Elmslie, F.V. et al. Alagille syndrome: family studies. J. Med. Genet. 32, 264–268 (1995).

    Article  CAS  Google Scholar 

  6. Byrne, J.L., Harrod, M.J., Friedman, J.M. & Howard-Peebles, P.N. Del(20p) with manifestations of arteriohepatic dysplasia. Am. J. Med. Genet. 24, 673–678 (1986).

    Article  CAS  Google Scholar 

  7. Anad, F. et al. Alagille syndrome and deletion of 20p. J. Med. Genet. 27, 729–737 (1990).

    Article  CAS  Google Scholar 

  8. Legius, E. et al. Alagille syndrome (arteriohepatic dysplasia) and del(20)(p11.2). Am. J. Med. Genet. 35, 532–535 (1990).

    Article  CAS  Google Scholar 

  9. Teebi, A.S., Murthy, D.S., Ismail, E.A. & Redha, A.A. Alagille syndrome with de novo del(20)(p11.2). Am. J. Med. Genet. 42, 35–38 (1992).

    Article  CAS  Google Scholar 

  10. Deleuze, J.F., Hazan, J., Dhorne, S., Weissenbach, J. & Hadchouel, M. Mapping of microsatellite markers in the Alagille region and screening of microdeletions by genotyping 23 patients. Eur. J. Hum. Genet. 2, 185–190 (1994).

    Article  CAS  Google Scholar 

  11. Hoi, F.A. et al. Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family. Hum. Genet. 95, 687–690 (1995).

    Google Scholar 

  12. Spinner, N.B. et al. Cytologically balanced t(2;20) in a two-generation family with Alagille syndrome: cytogenetic and molecular studies. Am. J. Hum. Genet. 55, 238–243 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hattori, M. et al. Alagille syndrome with t(3;20)(q13.3;p12.2). Nippon Shonika Gakkai Zasshi 99, 1984–1986 (1995).

    Google Scholar 

  14. Spinner, N.B. et al. Defining the Alagille syndrome critical region on 20p using a translocation breakpoint and overlapping deletions. Am. J. Hum. Genet. 57, A35 (1995).

    Article  Google Scholar 

  15. Krantz, I.D. et al. Investigation of SNAP-25 and PLCB4 as candidate genes for Alagille syndrome. Cytogenet. Cell. Genet. 74, 304–304 (1996).

    Google Scholar 

  16. Krantz, I.D. et al. Narrowing of the Alagille syndrome critical region and analysis of SNAP as a candidate gene. Am. J. Hum. Genet. 59, A224 (1996).

    Google Scholar 

  17. Pollet, N. et al. Construction of a 3.7-Mb physical map within human chromosome 20p12 ordering 18 markers in the Alagille syndrome locus. Genomics 27, 467–474 (1995).

    Article  CAS  Google Scholar 

  18. Oda, T., Elkahloun, A.G., Meltzer, P.S. & Chandrasekharappa, S.C. Identification and cloning of the human homolog (JAG1) of the rat Jagged gene from the Alagille syndrome critical region at 20p12. Genomics (in the press).

  19. Schnittger, S., Hofers, C., Heidemann, P., Beermann, F. & Hansmann, I. Molecular and cytogenetic analysis of an interstitial 20p deletion associated with syndromic intrahepatic ductular hypoplasia (Alagille syndrome). Hum. Genet. 83, 239–244 (1989).

    Article  CAS  Google Scholar 

  20. Desmaze, C. et al. Screening of microdeletions of chromosome 20 in patients with Alagille syndrome.. j. Med. Genet. 29, 233–235 (1992).

    Article  CAS  Google Scholar 

  21. Deleuze, J.F. et al. Deleted chromosome 20 from a patient with Alagille syndrome isolated in a cell hybrid through leucine transport selection: study of three candidate genes. Mamm. Genome. 5, 663–669 (1994).

    Article  CAS  Google Scholar 

  22. Rand, E.B., Spinner, N.B., Piccoli, D.A., Whitington, P.F. & Taub, R. Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p 12. Am. J. Hum. Genet. 57, 1068–1073 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, L. et al. Alagille syndrome is caused by mutations in Jag1, a ligand for Notch1. Nat. Genet. 16, 243–251 (1997).

    Article  CAS  Google Scholar 

  24. Spinner, N.B. et al. Mapping the Alagille syndrome critical region within 20p12. Proc. Single Chromosome 20 Workshop, February 1997, Hinxton, Cambridgeshire, UK Cytogenet. Cell. Genet. (in the press).

  25. Heitzler, P. & Simpson, P. The choice of cell fate in the epidermis of Drosophila. Cell 64, 1083–1092 (1991).

    Article  CAS  Google Scholar 

  26. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M.E. Notch signaling. Science 268, 225–232 (1995).

    Article  CAS  Google Scholar 

  27. Nye, J.S. & Kopan, R. Developmental signaling. Vertebrate ligands for Notch. Curr. Bib. 5, 966–969 (1995).

    Article  CAS  Google Scholar 

  28. Hunter, T. Oncoprotein networks. Cell 88, 333–346 (1997).

    Article  CAS  Google Scholar 

  29. Ellisen, L.W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).

    Article  CAS  Google Scholar 

  30. Joutel, A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707–710 (1996).

    Article  CAS  Google Scholar 

  31. Lindsell, C.E., Shawber, C.J., Boulter, J. & Weinmaster, G. Jagged: a mammalian ligand that activates Notch1. Cell 80, 909–917 (1995).

    Article  CAS  Google Scholar 

  32. Shawber, C.J., Boulter, J., Lindsell, C.E. & Weinmaster, G. Jagged2: A Serrate-like gene expressed during rat embryogenesis. Dev. Biol. 180, 370–376 (1996).

    Article  CAS  Google Scholar 

  33. Lindsell, C.E., Boulter, J., diSibio, G., Gossler, A. & Weinmaster, G. Expression patterns of Jagged, Deltal, Notchl, Notch2, and Notch3 genes identify ligand-receptor pairesthat may function in neural development. Mol. Cell. Neurosci. 8, 14–27 (1996).

    Article  CAS  Google Scholar 

  34. Bao, Z.Z. & Cepko, C.L. The expression and function of Notch pathway genes in the developing rat eye. J. Neurosci. 17, 1425–1434 (1997).

    Article  CAS  Google Scholar 

  35. Garrod, A. The lessons of rare maladies. Lancet. 1, 1055–1066 (1928).

    Article  Google Scholar 

  36. Elkahloun, A.G., Bittner, M., Hoskins, K., Gemmill, R. & Meltzer, P.S. Molecular cytogenetic characterization and physical mapping of 12q13-15 amplification in human cancers. Genes. Chromosomes. Cancer 17, 205–214 (1996).

    Article  CAS  Google Scholar 

  37. Beaudet, A.L. & Tsui, L.-C. A suggested nomenclature for designating mutations. Hum. Mutat. 2, 245–248 (1993).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Gene Transfer, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4442, USA

    Takaya Oda, Brian L. Pike, Francis S. Collins & Settara C. Chandrasekharappa

  2. Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4442, USA

    Abdel G. Elkahloun & Paul S. Meltzer

  3. Department of Pediatrics, Nagoya City University, Medical School, Nagoya, 467, Japan

    Kazuki Okajima

  4. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104-4399, USA

    Ian D. Krantz, Anna Genin, David A. Piccoli & Nancy B. Spinner

  5. Research Genetics Inc., Huntsville, Alabama, 35801, USA

    Abdel G. Elkahloun

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  1. Takaya Oda
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Correspondence to Francis S. Collins.

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Oda, T., Elkahloun, A., Pike, B. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16, 235–242 (1997). https://doi.org/10.1038/ng0797-235

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