Novel Heterozygous Mutations in<i> JAG1</i> and<i> NOTCH2</i> Genes in a Neonatal Patient with Alagille Syndrome

Brennan, Alisa K.; Kesavan, Anil

doi:10.1155/2017/1368189

Cited by 7 publications

(10 citation statements)

References 10 publications

(58 reference statements)

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“…According to the ACMG guidelines, they are pathogenic and strongly affect the JAG1 protein [25]. This coincided with previous reports [3,24,31]. All detected mutations are novel variants and were not found in GnomAD exomes, and different prediction software suggested the pathogenic effect of all mutations.…”

Section: Discussionsupporting

confidence: 87%

Broadening the clinical spectrum of ALGS: an Egyptian cohort with five novel mutations in JAG1 gene

Khairat

El‐Karaksy

El-Bassyouni

et al. 2022

Egypt J Med Hum Genet

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Background Alagille syndrome (ALGS) is a rare autosomal dominant multisystem disorder that affects the liver, heart, eyes, vertebrae, and kidneys and is associated with characteristic facies. This work aimed to study the spectrum of the clinical features of ALGS in an Egyptian cohort of patients in conjunction with partial sequencing of the JAG1 gene. Methods This study included 17 pediatric ALGS patients diagnosed on clinical grounds: facial features, cholestatic liver disease, and cardiac, vertebral, and ocular findings. Molecular analysis was conducted in 10 selected exons of the JAG1 gene. Results The clinical features of ALGS included cholestatic liver disease (100%), facial dysmorphism (100%), cardiac abnormalities (88.2%), butterfly vertebrae (64.7%), posterior embryotoxon (35.2%), poor growth (41%), xanthomata (11.8%), and hiatus hernia (11.8%). Five novel pathogenic JAG1 mutations were identified in this study, including two nonsense mutations, one splicing mutation, one frameshift insertion, and one frameshift deletion. In two patients, the mutations were confirmed to be de novo, as the mutations could not be detected in both parents. Conclusion Five novel JAG1 pathogenic variants were identified in this study. This is the first molecular study to report pathogenic mutations in the JAG1 gene within an Egyptian cohort of children with ALGS.

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Section: Discussionsupporting

confidence: 87%

Broadening the clinical spectrum of ALGS: an Egyptian cohort with five novel mutations in JAG1 gene

Khairat

El‐Karaksy

El-Bassyouni

et al. 2022

Egypt J Med Hum Genet

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“…Haploinsufficiency of NOTCH signaling components also leads to the development of Alagille syndrome (AGS) that affects multiple organs including the liver, heart, eye, kidney, and bone. AGS patients are reported to carry heterozygous mutation of Jag-1 ( Warthen et al, 2006 ) or Notch-2 ( McDaniell et al, 2006 ) or both ( Brennan and Kesavan, 2017 ). Mice models with heterozygous mutations of Jag-1 and Notch-2 also successfully recapitulated certain symptoms of AGS ( McCright et al, 2002 ), suggesting that reduction of NOTCH signaling leads to the development of AGS.…”

Section: Developmental Processes Sensitive To Notch Signaling Strength Perturbationmentioning

confidence: 99%

Biological Significance of NOTCH Signaling Strength

Shen

Huang

Wang

2021

Front. Cell Dev. Biol.

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The evolutionarily conserved NOTCH signaling displays pleotropic functions in almost every organ system with a simple signaling axis. Different from many other signaling pathways that can be amplified via kinase cascades, NOTCH signaling does not contain any intermediate to amplify signal. Thus, NOTCH signaling can be activated at distinct signaling strength levels, disruption of which leads to various developmental disorders. Here, we reviewed mechanisms establishing different NOTCH signaling strengths, developmental processes sensitive to NOTCH signaling strength perturbation, and transcriptional regulations influenced by NOTCH signaling strength changes. We hope this could add a new layer of diversity to explain the pleotropic functions of NOTCH signaling pathway.

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“…MDK has also been shown to cleave the cytoplasmic domain of Notch 2 which induces expression of Hes1 and NF-κB [ 49 ]. Mutations in Notch-2 or downstream targets have been associated with congenital heart malformations [ 50 , 51 ]. In addition, the Notch-2 signaling pathway induces angiogenesis and can allow proliferation of cardiomyocytes [ 52 , 53 , 54 ].…”

Section: Circulating Mdkmentioning

confidence: 99%

Midkine’s Role in Cardiac Pathology

Woulfe

Sucharov

2017

JCDD

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Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF.

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Novel Heterozygous Mutations in JAG1 and NOTCH2 Genes in a Neonatal Patient with Alagille Syndrome

Cited by 7 publications

References 10 publications

Broadening the clinical spectrum of ALGS: an Egyptian cohort with five novel mutations in JAG1 gene

Broadening the clinical spectrum of ALGS: an Egyptian cohort with five novel mutations in JAG1 gene

Biological Significance of NOTCH Signaling Strength

Midkine’s Role in Cardiac Pathology

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