The Genetics and Ocular Findings of Alagille Syndrome

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
Seminars in Ophthalmology (Impact Factor: 0.86). 10/2007; 22(4):205-10. DOI: 10.1080/08820530701745108
Source: PubMed


Alagille syndrome is an autosomal dominant disorder caused by mutations in the JAG1 gene. The JAG1 gene encodes a ligand for the Notch receptor and thus is part of a critical signaling pathway during development. The ophthalmologist can play an important role in the diagnosis of Alagille syndrome by identifying the characteristic ocular findings. These include a posterior embryotoxon, optic disc drusen, angulated retinal vessels, and a pigmentary retinopathy. Despite recent advances in the genetics of Alagille syndrome, the correlations between genotypes and phenotypes remain incompletely defined.

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    • "Classic features include intrahepatic bile-duct hypoplasia causing neonatal cholestatic jaundice, cardiovascular defects, skeletal abnormalities and a characteristic facial appearance [2]. Additional common findings include renal abnormalities, growth retardation and mental retardation [3]. Alagille syndrome is also associated with ocular abnormalities, most commonly with posterior embryotoxon, which is present in 95% of cases and is considered a major feature of this disorder [4]. "
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    ABSTRACT: To report the occurrence of xerophthalmia and keratomalacia in a patient with Alagille syndrome. The patient's record and relevant literature were reviewed. A 3-year-old boy with Alagille syndrome was examined at our institution due to severe bilateral ocular irritation. A corneal ulcer and keratomalacia were found in the right eye and severe dryness with corneal opacification was found in the left eye. He was treated with topical fortified antibiotics in the right eye, followed by amniotic membrane transplantation. Due to his systemic condition, characterized by severe cholestasis and intestinal malabsorption, a suspicion of vitamin A deficiency was raised and was later confirmed in serum analysis. This is the first report of xerophthalmia in a patient with Alagille syndrome. Vitamin A deficiency leading to xerophthalmia is common in developing countries; however, its occurrence in the West is rare, leading to a reduced awareness of this disorder amongst clinicians. Unusual eating habits, intestinal malabsorption and liver disease are possible causes for such a deficiency. The purpose of this case report is to raise awareness to the possibility of vitamin A deficiency in children with keratopathy, especially when associated with these disorders.
    Case Reports in Ophthalmology 09/2013; 4(3):311-5. DOI:10.1159/000357642
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    • "Furthermore, Jagged- 1(Jag1), a vertebrate homolog of the Drosophila ventral eye gene Ser, shows a DV asymmetric expression pattern in the retina. Moreover, the loss-of-function of Jag1 results in Alagille's syndrome, which also affects the eye (Oda et al., 1997; Xue et al., 1999; Kim and Fulton, 2007). Interestingly , it has been shown that mouse retina also begins with a default ventral-like state (Murali et al., 2005). "
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    ABSTRACT: During organogenesis in all multi-cellular organisms, axial patterning is required to transform a single layer organ primordium into a three-dimensional organ. The Drosophila eye model serves as an excellent model to study axial patterning. Dorso-ventral (DV) axis determination is the first lineage restriction event during axial patterning of the Drosophila eye. The early Drosophila eye primordium has a default ventral fate, and the dorsal eye fate is established by onset of dorsal selector gene pannier (pnr) expression in a group of cells on the dorsal eye margin. The boundary between dorsal and ventral compartments called the equator is the site for Notch (N) activation, which triggers cell proliferation and differentiation. This review will focus on (1) chronology of events during DV axis determination; (2) how early division of eye into dorsal and ventral compartments contributes towards the growth and patterning of the fly retina, and (3) functions of DV patterning genes.
    Developmental Dynamics 01/2012; 241(1):69-84. DOI:10.1002/dvdy.22764 · 2.38 Impact Factor
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    ABSTRACT: Intrinsically disordered proteins (IDPs) constitute a recently recognized realm of atypical biologically active proteins that lack stable structure under physiological conditions, but are commonly involved in such crucial cellular processes as regulation, recognition, signaling and control. IDPs are very common among proteins associated with various diseases. Recently, we performed a systematic bioinformatics analysis of the human diseasome, a network that linked the human disease phenome (which includes all the human genetic diseases) with the human disease genome (which contains all the disease-related genes) (Goh, K. I., Cusick, M. E., Valle, D., Childs, B., Vidal, M., and Barabasi, A. L. (2007). The human disease network. Proc. Natl. Acad. Sci. U.S.A. 104, 8685-90). The analysis of this diseasome revealed that IDPs are abundant in proteins linked to human genetic diseases, and that different genetic disease classes varied dramatically in the IDP content (Midic U., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2009) Protein disorder in the human diseasome: Unfoldomics of human genetic diseases. BMC Genomics. In press). Furthermore, many of the genetic disease-related proteins were shown to contain at least one molecular recognition feature, which is a relatively short loosely structured protein region within a mostly disordered segment with the feature gaining structure upon binding to a partner. Finally, alternative splicing was shown to be abundant among the diseasome genes. Based on these observations the human-genetic-disease-associated unfoldome was created. This minireview describes several illustrative examples of ordered and intrinsically disordered members of the human diseasome.
    Protein and Peptide Letters 12/2009; 16(12):1533-47. DOI:10.2174/092986609789839377 · 1.07 Impact Factor
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