Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Jun;62(6):1361–1369. doi: 10.1086/301875

Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.

I D Krantz 1, R P Colliton 1, A Genin 1, E B Rand 1, L Li 1, D A Piccoli 1, N B Spinner 1
PMCID: PMC1377154  PMID: 9585603

Abstract

Alagille syndrome (AGS) is a dominantly inherited disorder characterized by liver disease in combination with heart, skeletal, ocular, facial, renal, and pancreatic abnormalities. We have recently demonstrated that Jagged1 (JAG1) is the AGS gene. JAG1 encodes a ligand in the Notch intercellular signaling pathway. AGS is the first developmental disorder to be associated with this pathway and the first human disorder caused by a Notch ligand. We have screened 54 AGS probands and family members to determine the frequency of mutations in JAG1. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations within JAG1, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exceptions of a 5-bp deletion in exon 16, seen in two unrelated patients, and a C insertion at base 1618 in exon 9, also seen in two unrelated patients. The 35 intragenic mutations included 9 nonsense mutations (26%); 2 missense mutations (6%); 11 small deletions (31%), 8 small insertions (23%), and 1 complex rearrangement (3%), all leading to frameshifts; and 4 splice-site mutations (11%). The mutations are spread across the coding sequence of the gene within the evolutionarily conserved motifs of the JAG1 protein. There is no phenotypic difference between patients with deletions of the entire JAG1 gene and those with intragenic mutations, which suggests that one mechanism involved in AGS is haploinsufficiency. The two missense mutations occur at the same amino acid residue. The mechanism by which these missense mutations lead to the disease is not yet understood; however, they suggest that mechanisms other than haploinsufficiency may result in the AGS phenotype.

Full Text

The Full Text of this article is available as a PDF (671.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alagille D., Estrada A., Hadchouel M., Gautier M., Odièvre M., Dommergues J. P. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987 Feb;110(2):195–200. doi: 10.1016/s0022-3476(87)80153-1. [DOI] [PubMed] [Google Scholar]
  2. Alagille D., Odièvre 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. 1975 Jan;86(1):63–71. doi: 10.1016/s0022-3476(75)80706-2. [DOI] [PubMed] [Google Scholar]
  3. Anad F., Burn J., Matthews D., Cross I., Davison B. C., Mueller R., Sands M., Lillington D. M., Eastham E. Alagille syndrome and deletion of 20p. J Med Genet. 1990 Dec;27(12):729–737. doi: 10.1136/jmg.27.12.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Artavanis-Tsakonas S., Matsuno K., Fortini M. E. Notch signaling. Science. 1995 Apr 14;268(5208):225–232. doi: 10.1126/science.7716513. [DOI] [PubMed] [Google Scholar]
  5. Beaudet A. L., Tsui L. C. A suggested nomenclature for designating mutations. Hum Mutat. 1993;2(4):245–248. doi: 10.1002/humu.1380020402. [DOI] [PubMed] [Google Scholar]
  6. Becker K. F., Reich U., Handschuh G., Dalke C., Höfler H. Non-radioactive protein truncation test (nrPTT) for rapid detection of gene mutations. Trends Genet. 1996 Jul;12(7):250–250. doi: 10.1016/s0168-9525(96)90032-3. [DOI] [PubMed] [Google Scholar]
  7. Byrne J. L., Harrod M. J., Friedman J. M., Howard-Peebles P. N. del(20p) with manifestations of arteriohepatic dysplasia. Am J Med Genet. 1986 Aug;24(4):673–678. doi: 10.1002/ajmg.1320240411. [DOI] [PubMed] [Google Scholar]
  8. 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. 1977 May;52(5):360–367. doi: 10.1136/adc.52.5.360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dhorne-Pollet S., Deleuze J. F., Hadchouel M., Bonaïti-Pellié C. Segregation analysis of Alagille syndrome. J Med Genet. 1994 Jun;31(6):453–457. doi: 10.1136/jmg.31.6.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ellisen L. W., Bird J., West D. C., Soreng A. L., Reynolds T. C., Smith S. D., Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991 Aug 23;66(4):649–661. doi: 10.1016/0092-8674(91)90111-b. [DOI] [PubMed] [Google Scholar]
  11. Elmslie F. V., Vivian A. J., Gardiner H., Hall C., Mowat A. P., Winter R. M. Alagille syndrome: family studies. J Med Genet. 1995 Apr;32(4):264–268. doi: 10.1136/jmg.32.4.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hol F. A., Hamel B. C., Geurds M. P., Hansmann I., Nabben F. A., Daniëls O., Mariman E. C. Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family. Hum Genet. 1995 Jun;95(6):687–690. doi: 10.1007/BF00209488. [DOI] [PubMed] [Google Scholar]
  13. Joutel A., Corpechot C., Ducros A., Vahedi K., Chabriat H., Mouton P., Alamowitch S., Domenga V., Cécillion M., Marechal E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24;383(6602):707–710. doi: 10.1038/383707a0. [DOI] [PubMed] [Google Scholar]
  14. Kopan R., Weintraub H. Mouse notch: expression in hair follicles correlates with cell fate determination. J Cell Biol. 1993 May;121(3):631–641. doi: 10.1083/jcb.121.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Krantz I. D., Piccoli D. A., Spinner N. B. Alagille syndrome. J Med Genet. 1997 Feb;34(2):152–157. doi: 10.1136/jmg.34.2.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Krantz I. D., Rand E. B., Genin A., Hunt P., Jones M., Louis A. A., Graham J. M., Jr, Bhatt S., Piccoli D. A., Spinner N. B. Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet. 1997 May 2;70(1):80–86. [PubMed] [Google Scholar]
  17. Legius E., Fryns J. P., Eyskens B., Eggermont E., Desmet V., de Bethune G., Van den Berghe H. Alagille syndrome (arteriohepatic dysplasia) and del(20)(p11.2) Am J Med Genet. 1990 Apr;35(4):532–535. doi: 10.1002/ajmg.1320350419. [DOI] [PubMed] [Google Scholar]
  18. Li L., Krantz I. D., Deng Y., Genin A., Banta A. B., Collins C. C., Qi M., Trask B. J., Kuo W. L., Cochran J. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997 Jul;16(3):243–251. doi: 10.1038/ng0797-243. [DOI] [PubMed] [Google Scholar]
  19. Lindsell C. E., Shawber C. J., Boulter J., Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell. 1995 Mar 24;80(6):909–917. doi: 10.1016/0092-8674(95)90294-5. [DOI] [PubMed] [Google Scholar]
  20. Muskavitch M. A. Delta-notch signaling and Drosophila cell fate choice. Dev Biol. 1994 Dec;166(2):415–430. doi: 10.1006/dbio.1994.1326. [DOI] [PubMed] [Google Scholar]
  21. Oda T., Elkahloun A. G., Pike B. L., Okajima K., Krantz I. D., Genin A., Piccoli D. A., Meltzer P. S., Spinner N. B., Collins F. S. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997 Jul;16(3):235–242. doi: 10.1038/ng0797-235. [DOI] [PubMed] [Google Scholar]
  22. Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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 20p12. Am J Hum Genet. 1995 Nov;57(5):1068–1073. [PMC free article] [PubMed] [Google Scholar]
  24. Robey E., Chang D., Itano A., Cado D., Alexander H., Lans D., Weinmaster G., Salmon P. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell. 1996 Nov 1;87(3):483–492. doi: 10.1016/s0092-8674(00)81368-9. [DOI] [PubMed] [Google Scholar]
  25. Roest P. A., Roberts R. G., Sugino S., van Ommen G. J., den Dunnen J. T. Protein truncation test (PTT) for rapid detection of translation-terminating mutations. Hum Mol Genet. 1993 Oct;2(10):1719–1721. doi: 10.1093/hmg/2.10.1719. [DOI] [PubMed] [Google Scholar]
  26. Schnittger S., Höfers 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. 1989 Oct;83(3):239–244. doi: 10.1007/BF00285164. [DOI] [PubMed] [Google Scholar]
  27. Shulman S. A., Hyams J. S., Gunta R., Greenstein R. M., Cassidy S. B. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. 1984 Oct;19(2):325–332. doi: 10.1002/ajmg.1320190215. [DOI] [PubMed] [Google Scholar]
  28. Spinner N. B., Rand E. B., Fortina P., Genin A., Taub R., Semeraro A., Piccoli D. A. Cytologically balanced t(2;20) in a two-generation family with alagille syndrome: cytogenetic and molecular studies. Am J Hum Genet. 1994 Aug;55(2):238–243. [PMC free article] [PubMed] [Google Scholar]
  29. Sun X., Artavanis-Tsakonas S. The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands. Development. 1996 Aug;122(8):2465–2474. doi: 10.1242/dev.122.8.2465. [DOI] [PubMed] [Google Scholar]
  30. 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. 1992 Jan 1;42(1):35–38. doi: 10.1002/ajmg.1320420109. [DOI] [PubMed] [Google Scholar]
  31. Zhang F., Deleuze J. F., Aurias A., Dutrillaux A. M., Hugon R. N., Alagille D., Thomas G., Hadchouel M. Interstitial deletion of the short arm of chromosome 20 in arteriohepatic dysplasia (Alagille syndrome). J Pediatr. 1990 Jan;116(1):73–77. doi: 10.1016/s0022-3476(05)81648-8. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES