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Pilia, G. et al. Jagged-1 mutation analysis in Italian Alagille syndrome patients. Hum. Mutat. 14, 394-400

Istituto di Ricerca sulle Talassemie ed Anemie Mediterranee CNR, Cagliari, Italy.
Human Mutation (Impact Factor: 5.05). 11/1999; 14(5):394-400. DOI: 10.1002/(SICI)1098-1004(199911)14:5<394::AID-HUMU5>3.0.CO;2-1
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ABSTRACT Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.

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    • "53, 54 g patients from previous studies eveluated again in this study Over 440 various JAG1 mutations have already been described in ALGS patients. The most common are frameshift mutations (49 %), followed by nonsense mutations (16 %), missense mutations (15 %), gross deletions and insertions (11 %), while the least frequent variants are splice site mutations (9 %) (Li et al. 1997; Oda et al. 1997; Krantz et al. 1998; Yuan et al. 1998, 2001; Crosnier et al. 1999, 2000; Onouchi et al. 1999; Pilia et al. 1999; Heritage et al. 2000, 2002; Colliton et al. 2001; Giannakudis et al. 2001; Röpke et al. 2003; Jurkiewicz et al. 2005; Warthen et al. 2006; Kamath et al. 2009; Guegan et al. 2012; Lin et al. 2012; Wang et al. 2012). The spectrum of JAG1 mutations in the Polish ALGS patients presents a similar pattern to those from other groups, with only slight differences in the frequency of some types of mutations. "
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    ABSTRACT: Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94 %) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1 %) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. 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. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations.
    Journal of applied genetics 04/2014; 55(3). DOI:10.1007/s13353-014-0212-2 · 1.90 Impact Factor
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    • "In some cases, the deletion of chromosome 20 can be detected by standard cytogenetic analysis [Byrne et al., 1986; Schnittger et al., 1989; Anad et al., 1990; Legius et al., 1990; Zhang et al., 1990; Teebi et al., 1992], while in others the deletion is submicroscopic [Rand et al., 1995; Oda et al., 1997; Pilia et al., 1999]. We describe a girl with AGS caused by a deletion of 20p12 encompassing the JAG1 gene, detected by fluorescence in situ hybridization (FISH). "
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    ABSTRACT: We report an 18-month-old girl with Alagille syndrome, caused by a submicroscopic deletion of chromosome 20p, including the Jagged1 (JAG1) gene. FISH using a BAC probe containing JAG1 identified the deletion. Chromosomes were normal at the 550 band level. The deletion was inherited from her phenotypically normal mother who was found to have the deletion in 9/20 cells studied from peripheral blood. This is the first report of a JAG1 deletion inherited from an apparently unaffected mosaic parent.
    American Journal of Medical Genetics 10/2002; 112(2):190-3. DOI:10.1002/ajmg.10616 · 3.23 Impact Factor
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    • "Jagged, which is a transmembrane ligand for the Notch signaling pathway [49], is induced by IL-1β. Interestingly, jagged-1 is important for epithelial–mesenchymal cell interaction in development [50], and mutations in the jagged gene lead to Alagille syndrome, a congenital connective tissue disorder whose hallmarks include craniofacial and vertebral deformities [51]. Zhao and colleagues [52] identified frizzled (denoted FZD2) as the human homologue of the Drosophila polarity-determining gene. "
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    Arthritis Research 02/2001; 3(6):381-8. DOI:10.1186/ar331
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