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. 2003 Dec;40(12):891–895. doi: 10.1136/jmg.40.12.891

Consequences of JAG1 mutations

B Kamath 1, L Bason 1, D Piccoli 1, I Krantz 1, N Spinner 1
PMCID: PMC1735339  PMID: 14684686

Abstract

Background: Alagille syndrome (AGS) is a multi-system, autosomal dominant disorder with highly variable expressivity, caused by mutations within the Jagged1 (JAG1) gene.

Methods: We studied 53 mutation positive relatives of 34 AGS probands to ascertain the frequency of clinical findings in JAG1 mutation carriers.

Results: Eleven of 53 (21%) mutation positive relatives had clinical features that would have led to a diagnosis of AGS. Seventeen of the 53 (32%) relatives had mild features of AGS, revealed only after targeted evaluation following the diagnosis of a proband in their family. Twenty five of the 53 (47%) mutation positive relatives did not meet clinical criteria, and two of these individuals had no features consistent with AGS at all. The frequency of cardiac and liver disease was notably lower in the relatives than in the probands, characterising the milder end of the phenotypic spectrum. The characteristic facies of AGS was the feature with the highest penetrance, occuring almost universally in mutation positive probands and relatives.

Conclusions: This study has implications for genetic counselling of families with AGS and JAG1 mutations.

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Selected References

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  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. Crosnier C., Driancourt C., Raynaud N., Dhorne-Pollet S., Pollet N., Bernard O., Hadchouel M., Meunier-Rotival M. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999 May;116(5):1141–1148. doi: 10.1016/s0016-5085(99)70017-x. [DOI] [PubMed] [Google Scholar]
  3. Crosnier C., Lykavieris P., Meunier-Rotival M., Hadchouel M. Alagille syndrome. The widening spectrum of arteriohepatic dysplasia. Clin Liver Dis. 2000 Nov;4(4):765–778. doi: 10.1016/s1089-3261(05)70140-9. [DOI] [PubMed] [Google Scholar]
  4. Eldadah Z. A., Hamosh A., Biery N. J., Montgomery R. A., Duke M., Elkins R., Dietz H. C. Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet. 2001 Jan 15;10(2):163–169. doi: 10.1093/hmg/10.2.163. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Emerick K. M., Rand E. B., Goldmuntz E., Krantz I. D., Spinner N. B., Piccoli D. A. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999 Mar;29(3):822–829. doi: 10.1002/hep.510290331. [DOI] [PubMed] [Google Scholar]
  7. Hoffenberg E. J., Narkewicz M. R., Sondheimer J. M., Smith D. J., Silverman A., Sokol R. J. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. 1995 Aug;127(2):220–224. doi: 10.1016/s0022-3476(95)70298-9. [DOI] [PubMed] [Google Scholar]
  8. Kamath Binita M., Krantz Ian D., Spinner Nancy B., Heubi James E., Piccoli David A. Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance. Am J Med Genet. 2002 Oct 1;112(2):194–197. doi: 10.1002/ajmg.10610. [DOI] [PubMed] [Google Scholar]
  9. Kamath Binita M., Loomes Kathleen M., Oakey Rebecca J., Emerick Karan E. M., Conversano Tracy, Spinner Nancy B., Piccoli David A., Krantz Ian D. Facial features in Alagille syndrome: specific or cholestasis facies? Am J Med Genet. 2002 Oct 1;112(2):163–170. doi: 10.1002/ajmg.10579. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Laufer-Cahana Ayala, Krantz Ian D., Bason Lynn D., Lu Feng-Min, Piccoli David A., Spinner Nancy B. Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. Am J Med Genet. 2002 Oct 1;112(2):190–193. doi: 10.1002/ajmg.10616. [DOI] [PubMed] [Google Scholar]
  13. Le Caignec C., Lefevre M., Schott J. J., Chaventre A., Gayet M., Calais C., Moisan J. P. Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1. Am J Hum Genet. 2002 May 17;71(1):180–186. doi: 10.1086/341327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Lykavieris P., Hadchouel M., Chardot C., Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001 Sep;49(3):431–435. doi: 10.1136/gut.49.3.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ming J. E., McDonald-McGinn D. M., Megerian T. E., Driscoll D. A., Elias E. R., Russell B. M., Irons M., Emanuel B. S., Markowitz R. I., Zackai E. H. Skeletal anomalies and deformities in patients with deletions of 22q11. Am J Med Genet. 1997 Oct 17;72(2):210–215. doi: 10.1002/(sici)1096-8628(19971017)72:2<210::aid-ajmg16>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Romanchuk K. G., Judisch G. F., LaBrecque D. R. Ocular findings in arteriohepatic dysplasia (Alagille's syndrome). Can J Ophthalmol. 1981 Apr;16(2):94–99. [PubMed] [Google Scholar]
  19. Sonel B., Yalçin P., Oztürk E. A., Bökesoy I. Butterfly vertebra: a case report. Clin Imaging. 2001 May-Jun;25(3):206–208. doi: 10.1016/s0899-7071(01)00266-2. [DOI] [PubMed] [Google Scholar]
  20. Spinner N. B., Colliton R. P., Crosnier C., Krantz I. D., Hadchouel M., Meunier-Rotival M. Jagged1 mutations in alagille syndrome. Hum Mutat. 2001;17(1):18–33. doi: 10.1002/1098-1004(2001)17:1<18::AID-HUMU3>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Watson G. H., Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. 1973 Jun;48(6):459–466. doi: 10.1136/adc.48.6.459. [DOI] [PMC free article] [PubMed] [Google Scholar]

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