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Alagille Syndrome Mimicking Biliary Atresia in Early Infancy.

Dědič T, Jirsa M, Keil R, Rygl M, Šnajdauf J, Kotalová R - PLoS ONE (2015)

Bottom Line: Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1.No mutations were found in the remaining 67 patients.Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.

ABSTRACT
Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we aimed to identify JAG1 mutations in newborns with proven biliary atresia (n = 72). Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1. No mutations were found in the remaining 67 patients. All "biliary atresia" carriers of JAG1 mutations developed typical Alagille syndrome at the age of three years. Our data do not support association of biliary atresia with JAG1 mutations, at least in Czech patients. Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.

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Schematic representation of the Jagged1 protein and spliced JAG1 mRNA with mutations found in our patients.
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pone.0143939.g001: Schematic representation of the Jagged1 protein and spliced JAG1 mRNA with mutations found in our patients.

Mentions: In contrast, three novel mutations were found in three index subjects and one sibling with typical features of Alagille syndrome at the age of six months (patients 6–9 in Table 2). All mutations present in heterozygous state are of maternal origin. The otherwise healthy mothers had craniofacial dysmorphic features. The two frameshift mutations create early stop codons and, provided that the mutated mRNA is not eliminated by nonsense-mediated decay, result in non-functional truncated proteins lacking the membrane and cytoplasmic domain (Fig 1). The missense mutation c.402G>T (p.Leu134Phe) affects exon 3, which encodes a part of the DSL domain of JAG1 (Fig 1). The domain is highly conserved between different species and is essential to activate Notch receptors [13]. The substitution of 134Leu with phenylalanine is predicted as pathogenic using the PredictSNP 1.0 classifier, the reliability of the prediction is 87% (S3 Table). The frameshift mutation p.Asp684fs found in patient 2 is also present in his symptomatic brother (patient 8 in Table 2). Both siblings differ in their clinical presentation (see Table 2); however, this is well in line with the known highly variable expressivity of the disease [14].


Alagille Syndrome Mimicking Biliary Atresia in Early Infancy.

Dědič T, Jirsa M, Keil R, Rygl M, Šnajdauf J, Kotalová R - PLoS ONE (2015)

Schematic representation of the Jagged1 protein and spliced JAG1 mRNA with mutations found in our patients.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664419&req=5

pone.0143939.g001: Schematic representation of the Jagged1 protein and spliced JAG1 mRNA with mutations found in our patients.
Mentions: In contrast, three novel mutations were found in three index subjects and one sibling with typical features of Alagille syndrome at the age of six months (patients 6–9 in Table 2). All mutations present in heterozygous state are of maternal origin. The otherwise healthy mothers had craniofacial dysmorphic features. The two frameshift mutations create early stop codons and, provided that the mutated mRNA is not eliminated by nonsense-mediated decay, result in non-functional truncated proteins lacking the membrane and cytoplasmic domain (Fig 1). The missense mutation c.402G>T (p.Leu134Phe) affects exon 3, which encodes a part of the DSL domain of JAG1 (Fig 1). The domain is highly conserved between different species and is essential to activate Notch receptors [13]. The substitution of 134Leu with phenylalanine is predicted as pathogenic using the PredictSNP 1.0 classifier, the reliability of the prediction is 87% (S3 Table). The frameshift mutation p.Asp684fs found in patient 2 is also present in his symptomatic brother (patient 8 in Table 2). Both siblings differ in their clinical presentation (see Table 2); however, this is well in line with the known highly variable expressivity of the disease [14].

Bottom Line: Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1.No mutations were found in the remaining 67 patients.Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.

ABSTRACT
Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we aimed to identify JAG1 mutations in newborns with proven biliary atresia (n = 72). Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1. No mutations were found in the remaining 67 patients. All "biliary atresia" carriers of JAG1 mutations developed typical Alagille syndrome at the age of three years. Our data do not support association of biliary atresia with JAG1 mutations, at least in Czech patients. Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.

Show MeSH
Related in: MedlinePlus