Alagille Syndrome: Genetics and Functional Models

Gilbert, Melissa A.; Spinner, Nancy B.

doi:10.1007/s40139-017-0144-8

Cited by 31 publications

(34 citation statements)

References 62 publications

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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%

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

et al. 2020

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Background and Aims Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y‐box 9) in late embryonic and neonatal livers of Jag1‐deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. Approach and Results Conditional removal of one copy of Sox9 in Jag1+/− livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/− livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/− livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5‐month‐old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/− mice without ectopic hepatocyte‐to‐cholangiocyte transdifferentiation or long‐term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. Conclusions Our results establish Sox9 as a dosage‐sensitive modifier of Jag1+/− liver phenotypes with a permissive role in biliary development. Our data further suggest that liver‐specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.

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Section: Sox9 Is a Modifier Of The Liver Disease Severity In A Mouse mentioning

confidence: 99%

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

et al. 2020

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“…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%

Alagille syndrome mutation update: Comprehensive overview ofJAG1andNOTCH2mutation frequencies and insight into missense variant classification

et al. 2019

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Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single‐center study, which includes 401 probands and 111 affected family members amassed over a 27‐year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.

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“…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%

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

Sullivan¹,

Motley²,

Johnson³

et al. 2020

Journal of Clinical Investigation

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Authorship note: JMS and WWM are co-first authors. Conflict of interest: WWM is currently an employee of Third Rock Ventures. JOJ is currently an employee of Quest Diagnostics. BJT has received grant support from Merck and Microsoft Research. BJT holds European Union (EP2751284A1, Method For Diagnosing A Neurodegenerative Disease) and US (20180187262) patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of the C9orf72 gene. CJS has received grant support from and holds patents (WO2016/164896 "Modulation of SMN expression," WO2017/21884 "Combinations for the Modulation of SMN expression") with Ionis Pharmaceuticals; has served as a paid advisor, consultant, and/or speaker for Biogen, PTC Therapeutics, Roche/Genentech, AveXis, and Cytokinetics; and is an associate editor for the JCI. This arrangement has been approved by Johns Hopkins University in accordance with its conflict of interest policies.

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Alagille Syndrome: Genetics and Functional Models

Cited by 31 publications

References 62 publications

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

Alagille syndrome mutation update: Comprehensive overview ofJAG1andNOTCH2mutation frequencies and insight into missense variant classification

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

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