A mouse model of Alagille syndrome:<i>Notch2</i>as a genetic modifier of<i>Jag1</i>haploinsufficiency

McCright, Brent; Lozier, Julie; Gridley, Thomas

doi:10.1242/dev.129.4.1075

Cited by 426 publications

(22 citation statements)

References 51 publications

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“…Previous studies have shown that NOTCH1 plays a role in mediating lateral inhibition postnatally, and in preventing continued proliferation [ 72 , 73 ]. NOTCH2 is also a possible receptor given that it acts as the receptor for JAG1 in other systems that are affected in Alagille syndrome [ 74 ]. Thus, NOTCH1 and NOTCH2 are possible receptors based on established roles in the cochlea or other systems, but NOTCH1, NOTCH2, NOTCH3, or a combination of these receptors, could mediate the effects of JAG1 in the maturing cochlea.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

et al. 2022

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The mammalian cochlea is an exceptionally well-organized epithelium composed of hair cells, supporting cells, and innervating neurons. Loss or defects in any of these cell types, particularly the specialized sensory hair cells, leads to deafness. The Notch pathway is known to play a critical role in the decision to become either a hair cell or a supporting cell during embryogenesis; however, little is known about how Notch functions later during cochlear maturation. Uniquely amongst Notch ligands, Jagged1 (JAG1) is localized to supporting cells during cell fate acquisition and continues to be expressed into adulthood. Here, we demonstrate that JAG1 in maturing cochlear supporting cells is essential for normal cochlear function. Specifically, we show that deletion of JAG1 during cochlear maturation disrupts the inner hair cell pathway and leads to a type of deafness clinically similar to auditory neuropathy. Common pathologies associated with disruptions in inner hair cell function, including loss of hair cells, synapses, or auditory neurons, were not observed in JAG1 mutant cochleae. Instead, RNA-seq analysis of JAG1-deficient cochleae identified dysregulation of the Rho GTPase pathway, known to be involved in stereocilia development and maintenance. Interestingly, the overexpression of one of the altered genes, Diaph3, is responsible for autosomal dominant auditory neuropathy-1 (AUNA1) in humans and mice, and is associated with defects in the inner hair cell stereocilia. Strikingly, ultrastructural analyses of JAG1-deleted cochleae revealed stereocilia defects in inner hair cells, including fused and elongated bundles, that were similar to those stereocilia defects reported in AUNA1 mice. Taken together, these data indicate a novel role for Notch signaling in normal hearing development through maintaining stereocilia integrity of the inner hair cells during cochlear maturation.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

et al. 2022

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“…AGS is a genetic disorder caused by mutations in JAG1 and NOTCH2, which are components of the NOTCH signaling pathway associated with the development of multiple organs, 18,19 including bile duct and cardiovascular system 20,21 Because the disease is most common in childhood and highly variable across patients, 22 AGS is underdiagnosed in adults, especially those without a family history. The patients in this study were from 16 to 56 years of age.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Alagille Syndrome in Adults

Li¹,

Wu²,

Chen³

et al. 2022

J Clin Transl Hepatol

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Background and Aims: Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series. Methods: Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed. Results: Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the JAG1 gene and four in the NOTCH2 gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time. Conclusions: The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing.

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“…If the first-degree relatives of the patient had been diagnosed with ALGS, then this is considered sufficient for the patient to be diagnosed with ALGS as long as the patient met the two classic criteria ( 8 , 9 ). NOTCH 2 gene mutation was identified as a pathogenic gene in the JAG1/NOTCH2 double heterozygous mouse model in 2002 ( 10 ). In 2006, McDaniell et al found that 5 out of 11 ALGS probands who were JAG 1 mutation-negative possessed a NOTCH 2 mutation and showed renal involvement, including small kidneys with cysts bilaterally and dysplastic kidneys ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

Pan

et al. 2022

Front. Pediatr.

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IntroductionHere, we report the case of an infant suffering from Alagille syndrome (ALGS), manifesting with the atypical clinical manifestations of prenatal oligohydramnios and renal lesions. To the best of our knowledge, this is the first case of ALGS presenting as prenatal oligohydramnios and renal lesions caused by a de novo variant of the NOTCH2 gene.Case presentationA 3-month-old male infant was hospitalized for severe malnutrition. He presented with prenatal oligohydramnios from 28+4 weeks of gestation. After birth, he failed to thrive and suffered from impaired motor development, thermoregulation disorders, congenital bilateral renal hypodysplasia, which initially manifested as stage 5 before improving to stage 3 chronic renal impairment, slightly elevated levels of transaminases, cholestasis, and dysmorphic facial features. We used a diagnostic screening panel of 4,047 pathogenic genes and whole exome sequencing (WES) to analyze the proband and his parents (who had normal kidneys). We found that the proband carried a de novo heterozygous splicing variant (c.5930-2A > G) in intron 33 of the NOTCH2 gene. Transcriptome sequencing confirmed that the mutation of this gene site would affect the splicing of NOTCH2 mRNA and lead to exon 33 skipping.ConclusionsOur case expands the spectrum of pathogenic variants of the NOTCH2 gene that are known to be associated with ALGS and characterized by prenatal oligohydramnios and renal lesions. It also reminds us of the necessity to monitor the liver and kidney function of the infant if a mother has oligohydramnios during pregnancy and we recommend ALGS as an additional differential diagnosis in prenatal renal abnormalities.

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A mouse model of Alagille syndrome:Notch2as a genetic modifier ofJag1haploinsufficiency

Cited by 426 publications

References 51 publications

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

Deletion of the Notch ligand Jagged1 during cochlear maturation leads to inner hair cell defects and hearing loss

Clinical and Genetic Characteristics of Alagille Syndrome in Adults

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

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