2017
DOI: 10.1007/s40139-017-0144-8
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Alagille Syndrome: Genetics and Functional Models

Abstract: Purpose of review We review the genetics of the autosomal dominant, multi-system disorder, Alagille syndrome and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion. Recent findings Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notc… Show more

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Cited by 36 publications
(34 citation statements)
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“…(4,12) A strong correlation has been established between a number of early life markers and the outcome of liver disease in patients with ALGS. (11) However, there is no genotype-phenotype correlation in ALGS, (11,(13)(14)(15) and the basis for variability in disease presentation and outcome is not known. Moreover, a mechanism-based therapy does not exist for the ALGS liver phenotypes.…”
Section: Sox9 Is a Modifier Of The Liver Disease Severity In A Mouse mentioning
confidence: 99%
“…(4,12) A strong correlation has been established between a number of early life markers and the outcome of liver disease in patients with ALGS. (11) However, there is no genotype-phenotype correlation in ALGS, (11,(13)(14)(15) and the basis for variability in disease presentation and outcome is not known. Moreover, a mechanism-based therapy does not exist for the ALGS liver phenotypes.…”
Section: Sox9 Is a Modifier Of The Liver Disease Severity In A Mouse mentioning
confidence: 99%
“…NOTCH2 also contains a series of Ankyrin (ANK) repeats, which are required for signal propagation and allow for the interaction of the intracellular region of NOTCH2 with transcription factors (Tamura et al, ). There have been many recent reviews on ALGS, JAG1 , and NOTCH2 that we recommend for additional reference (Bray, ; Gilbert & Spinner, ; Grochowski, Loomes, & Spinner, ; Saleh et al, ).…”
Section: Introductionmentioning
confidence: 99%
“…Both substitutions are predicted to be deleterious by in silico analyses (gnomAD). Dominant mutations in JAG1 have previously been shown to cause Alagille syndrome, which is characterized by defects in bile ducts, heart, kidney, facies, and vertebrae (4,5). There was no history of cardiac, kidney, or liver disease in affected individuals in either CMT2 family nor evidence of jaundice, xanthomas, or facial dysmorphology.…”
Section: Resultsmentioning
confidence: 99%
“…The vast majority of Alagille syndrome-causing mutations are JAG1 gene deletions or truncating mutations, suggesting that haploinsufficiency represents the primary disease mechanism (4, 5). The identification of Alagille syndrome-causing mutations in NOTCH2 further points to a key role of reduced JAG1/NOTCH2 signaling in disease pathogenesis (4,5). The specific involvement of peripheral nerve in CMT2 suggests that p.Ser577Arg and p.Ser650Pro may precipitate disease through a more complex, or tissue-specific, mechanism or mechanisms, potentially involving specific reductions or alterations in Notch receptor trans-activation and/or cis-inhibition.…”
Section: (Supplementalmentioning
confidence: 99%