Mutations in the human Jagged1 gene are responsible for Alagille syndrome

@article{Oda1997MutationsIT,
  title={Mutations in the human Jagged1 gene are responsible for Alagille syndrome},
  author={T. Oda and A. Elkahloun and B. Pike and K. Okajima and I. Krantz and A. Genin and D. Piccoli and P. Meltzer and N. Spinner and F. Collins and S. Chandrasekharappa},
  journal={Nature Genetics},
  year={1997},
  volume={16},
  pages={235-242}
}
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… Expand
Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
TLDR
Four distinct coding mutations in JAG1 are demonstrated, providing evidence that it is the causal gene for Alagille syndrome, and supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagile syndrome phenotype. Expand
Mutational analysis of the Jagged 1 gene in Alagille syndrome families.
TLDR
It is demonstrated that AGS is a dominant disease and suggested that the JAG1 gene exerts a fundamental role in regulating genes involved in development, and single-strand conformational polymorphism and DNA sequencing analysis are suggested. Expand
Jagged‐1 mutation analysis in Italian Alagille syndrome patients
TLDR
The hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis is supported, as the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations. Expand
Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome
TLDR
The JAG1 gene was investigated for genetic alterations in eight Japanese AGS patients, using fluorescence in situ hybridization, single strand conformation polymorphism (SSCP) analysis, and direct sequencing, and there was no apparent correlation between the genotypes of the patients and their affected organs. Expand
Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome.
TLDR
Most of the observed mutations other than the missense mutations in JAGGED1 are expected to give rise to truncated and unanchored proteins. Expand
Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families.
TLDR
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. Expand
Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome
TLDR
Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent and the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations. Expand
Clinical and molecular genetics of Alagille syndrome.
TLDR
There is no phenotypic difference between patients with deletion of the entire JAG1 gene and those with intragenic mutations, which suggests that haploinsufficiency for Jag1 is a mechanism causing AGS. Expand
Alagille Syndrome and JAGGED1/NOTCH Sequence
TLDR
The finding that mutations in JAGGED1 and NOTCH2 cause AGS indicates that Notch signaling is important in the development of the organ systems affected and leads to further insights into bile duct and cardiac development. Expand
Alagille syndrome associated with a paracentric inversion 20p12.2p13 disrupting the JAG1 gene.
TLDR
An unusual association between two most common causes of chronic liver disease in childhood, AGS and alpha-1-antitrypsin deficiency, as well as their influence on the proband's abnormal phenotype are discussed. Expand
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References

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Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
TLDR
Four distinct coding mutations in JAG1 are demonstrated, providing evidence that it is the causal gene for Alagille syndrome, and supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagile syndrome phenotype. Expand
Molecular analysis of 24 Alagille syndrome families identifies a single submicroscopic deletion and further localizes the Alagille region within 20p12.
TLDR
The additional finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS region are rare in cytogenetically normal patients with this disorder, suggesting that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome. Expand
Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12.
TLDR
The human Jagged1 (JAG1) appears to be a strong candidate gene for this disease, and full-length cDNA cloning, expression patterns, and precise physical location of this gene within the Alagille syndrome critical region are described. Expand
Cytologically balanced t(2;20) in a two-generation family with alagille syndrome: cytogenetic and molecular studies.
TLDR
A cytogenetic study of patients with Alagille syndrome identified a family in which a cytologically balanced translocation between chromosomes 2 and 20, 46,XX/XY, t(2;20)(q21.3;p12), is segregating concordantly with the disease. Expand
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TLDR
Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counselling and develop criteria for detecting the disorder in parents. Expand
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TLDR
Segregation analysis of AGS using 33 families collected through 43 probands concluded that AGS is transmitted as a dominant disorder with 94% penetrance and 15% of cases are sporadic. Expand
Mapping of Microsatellite Markers in the Alagille Region and Screening of Microdeletions by Genotyping 23 Patients
TLDR
The localisation of 5 microsatellite markers within the deletion of one AGS patient allows an estimation of the genetic extent of this deletion as being between 30 and 36 cM, and demonstrates its paternal origin. Expand
TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms
TLDR
It is shown that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch, which may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms. Expand
Molecular cytogenetic characterization and physical mapping of 12q13–15 amplification in human cancers
TLDR
The results suggest that the MDM2 and CDK4 regions may be either coamplified or amplified independently, and they illustrate how the map positions of genes and their functions may interact to determine the pattern of DNA amplification in human malignancies. Expand
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
TLDR
The characterization of the human Notch3 gene, which was previously mapped to the CADASIL critical region, is reported, indicating that Notch 3 could be the defective protein in CADASil patients. Expand
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