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JAGGED 1; JAG1

JAGGED 1; JAG1

Alternative titles; symbolsJAGL1HGNC Approved Gene Symbol: JAG1Cytogenetic location: 20p12.2 Genomic coordinates (GRCh38): 20:10,637,683-10,673,998 (from NCB...

Alternative titles; symbols

  • JAGL1

HGNC Approved Gene Symbol: JAG1

Cytogenetic location: 20p12.2 Genomic coordinates (GRCh38): 20:10,637,683-10,673,998 (from NCBI)

▼ Description
Jagged-1 is a ligand of the Notch receptor (see Notch1, 190198), and their binding triggers a cascade of proteolytic cleavage that eventually leads to the release of the intracellular part of the receptor from the membrane, allowing it to translocate to the nucleus and activate transcription factors that play key roles in cell differentiation and morphogenesis (Guarnaccia et al., 2004).

▼ Cloning and Expression
Notch proteins are a family of closely related transmembrane receptors demonstrated to be instrumental in cell fate decisions. Notch ligands 'Delta' and 'Jagged' (Lindsell et al., 1995) were identified in Drosophila and rat, respectively. Oda et al. (1997) isolated the human homolog of the rat Jagged gene (symbolized JAGL1 by them) from a CpG island in a YAC clone covering the Alagille syndrome (ALGS; 118450) critical region on 20p12. This region had been previously defined as flanked by SNAP (600322) distally and D20S186 proximally. The 5,942-bp cDNA possesses 3 alternative polyadenylation sites. Northern blot analysis of RNA from adult tissues indicated that JAGL1 is widely expressed in many tissues. The most abundant expression was observed in ovary, prostate, pancreas, placenta, and heart.

Gray et al. (1999) also cloned JAG1, which they called HJ1. Northern blot analysis revealed expression of a 6.6-kb JAG1 transcript in heart, placenta, and kidney, with weaker expression in lung, skeletal muscle, and pancreas. Immunohistochemical analysis demonstrated high expression of JAG1 in metastatic and nonmetastatic squamous epithelia, with upregulated expression in squamous cell carcinoma and in situ and invasive adenocarcinoma.

Loomes et al. (1999) demonstrated that the JAG1 gene is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in Alagille syndrome. Loomes et al. (2002) found that JAG1 is expressed in cells adjacent to those expressing Notch2 (600275), suggesting a possible ligand receptor interaction.

Jones et al. (2000) reported expression studies in human embryos aged 32 to 52 days using S-labeled riboprobes for JAG1 RNA. The JAG1 gene is expressed in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube. The authors concluded that the JAG1 gene is expressed in the structures affected in Alagille syndrome.

Guarnaccia et al. (2004) stated that JAG1 is a type I, membrane- anchored, multidomain protein. The extracellular part is made of a DSL domain, followed by a series of 16 EGF (131530)-like repeats, and a von Willebrand factor (613160) type C domain. They found that the C-terminal part of EGF repeat 1 and all of EGF repeat 2, encoded by exon 6, form an autonomously folding unit and is structured in solution.

▼ Gene Function
Bell et al. (2001) determined that JAG1 was 1 of several transcripts upregulated by umbilical vein endothelial cells during capillary morphogenesis in 3-dimensional collagen matrices.

Li et al. (2006) found that Jag1 activated Notch signaling in rats and enhanced the differentiation of mesenchymal stem cells into cardiomyocytes.

Rodilla et al. (2009) found that expression of JAG1 was elevated by the Wnt signaling molecules beta-catenin (CTNNB1; 116806) and TCF (see TCF4, or TCF7L2; 602228) in colorectal cancers, resulting in activation of the Notch signaling pathway in addition to the Wnt signaling pathway. Chromatin immunoprecipitation analysis revealed direct binding of beta-catenin to the promoter region of JAG1 in the colorectal tumor cell line Ls174T. Expression of dominant-negative TCF4 or inhibition of beta-catenin reduced JAG1 protein levels and activated NOTCH1. The activated NOTCH1 intracellular domain, in the absence of Wnt signaling, inhibited differentiation in Ls174T cells and promoted vasculogenesis in Ls174T-based tumors following injection in nude mice. In contrast, knockdown of JAG1 via small interfering RNA blocked expression of Wnt target genes in Ls174T cells, and deletion of a single Jag1 allele reduced tumor size in Apc (611731) mutant mice. High JAG1 expression correlated with nuclear beta-catenin staining in adenomas of familial adenomatous polyposis (FAP; 175100) patients. Rodilla et al. (2009) concluded that JAG1 is the pathologic link between Wnt and Notch signaling in colorectal cancer.

By microarray analysis, Hashimi et al. (2009) identified MIR21 (611020) and MIR34A (611172) among 20 miRNAs that were expressed in a stage-specific manner during differentiation of cultured human monocyte-derived dendritic cells (MDDCs). They also found that WNT1 (164820) was a functional target of MIR34A and that JAG1 was a functional target of both MIR21 and MIR34A. Inhibition of both MIR21 and MIR34A or overexpression of WNT1 and JAG1 stalled differentiation of MDDCs and reduced their endocytic capacity to levels characteristic of immature DCs. RT-PCR and Western blot analyses revealed that MIR21 and MIR34A functioned by translational suppression of WNT1 and JAG1.

To disrupt Jagged signaling acutely in adult mammals, Lafkas et al. (2015) generated antibody antagonists that selectively target JAG1 and JAG2 (602570) and determined a crystal structure that explains selectivity. Lafkas et al. (2015) showed that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrated a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Lafkas et al. (2015) concluded that their discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveiled unexpected plasticity, and established a model for Notch regulation of transdifferentiation.

▼ Gene Structure
Oda et al. (1997) determined that the JAGL1 gene extends over 36 kb and has 26 exons, ranging in size from 28 bp to 2,284 bp. Intron sizes vary from 89 bp to nearly 9 kb. A highly polymorphic CA dinucleotide repeat was detected in intron 19. This marker proved useful for the detection of submicroscopic deletions.

▼ Biochemical Features
Crystal Structure

Luca et al. (2017) determined the 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 (190198) complexed with an engineered, high-affinity variant of Jag1. The structure revealed a binding interface that extends approximately 120 angstroms along 5 consecutive domains of each protein. O-Linked fucose modifications on Notch1 epidermal growth factor-like (EGF) domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Delta-like 4 (DLL4; 605185) ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.

▼ Mapping
Using FISH, Gray et al. (1999) confirmed that the JAG1 gene maps to chromosome 20p12.

▼ Molecular Genetics
Alagille Syndrome

By SSCP analysis of the JAG1 coding region from patients with Alagille syndrome, Oda et al. (1997) found 3 variant patterns. The accompanying sequences contained a deletion (601920.0001), an insertion, and a splice donor mutation (601920.0002) in 3 unrelated ALGS patients. In a fourth kindred, a single nucleotide insertion was found in exon 22; in a fifth kindred a mutation in the donor splice site of intron 23 was discovered. Li et al. (1997) likewise demonstrated the localization of the JAG1 gene in the Alagille syndrome critical region within 20p12. They studied 4 families with ALGS and found a distinct coding mutation segregating with the disease phenotype in each (e.g., 601920.0003).

Krantz et al. (1998) screened 54 Alagille syndrome probands and family members to determine the frequency of mutations in the JAG1 gene. Three patients (6%) had deletions of the entire gene. Of the remaining 51 patients, 35 (69%) had mutations in the JAG1 gene, identified by SSCP analysis. Of the 35 identified intragenic mutations, all were unique, with the exception of a 5-bp deletion in exon 16 (601920.0007), seen in 2 unrelated patients, and a C insertion at base 1618 in exon 9 (601920.0008), also seen in 2 unrelated patients. The 35 intragenic mutations included 9 nonsense mutations (26%), 2 missense mutations (6%), 11 small deletions (31%), 8 small insertions (23%), and 1 complex rearrangement (3%), all leading to frameshifts. In addition, there were 4 splice site mutations (11%). The mutations were spread across the coding sequence of the gene within the evolutionarily conserved motifs of the JAG1 protein. There was no phenotypic difference between patients with deletions of the entire JAG1 gene and those with intragenic mutations, which suggests that 1 mechanism involved in ALGS is haploinsufficiency. The 2 missense mutations occurred in the same amino acid residue, arg184 to cys (601920.0005) and arg184 to his (601920.0006). The mechanism by which these missense mutations led to the disease was not understood; however, Krantz et al. (1998) suggested that mechanisms other than haploinsufficiency may result in the ALGS phenotype.

Cardiac defects are seen in more than 95% of ALGS patients. Most commonly these are right-sided defects ranging from mild peripheral pulmonic stenosis to severe forms of tetralogy of Fallot. ALGS demonstrates highly variable expressivity with respect to all of the involved systems. Krantz et al. (1999) hypothesized that defects in the JAG1 gene can be found in patients with presumably isolated heart defects, such as tetralogy of Fallot or pulmonic stenosis. In 1 patient, a 3.5-year-old female with a 4-generation history of pulmonic stenosis, they identified a 1-bp insertion (684insG; 601920.0009) in the JAG1 gene, resulting in a premature stop codon at amino acid 745. This patient was noted to have frontal bossing, deep-set eyes, broad nasal bridge, and pointed chin (consistent with the facial features of ALGS). The mutation was also identified in the patient's mother, who had pulmonic stenosis. Further studies after discovery of the JAG1 mutation showed posterior embryotoxon (which was also present in the mother) and moderately elevated liver enzyme levels. No vertebral defects were identified. A second patient with tetralogy of Fallot and a 'butterfly' vertebra on chest x-ray was found to have a deletion of the 20p12 region that encompasses the JAG1 gene.

Crosnier et al. (1999) searched the coding sequence of the JAG1 gene by single-strand conformation polymorphism and sequence analysis for mutations in 109 unrelated patients with Alagille syndrome and members of their families, if available. In 69 patients (63%), they found intragenic mutations, including 14 nonsense mutations, 31 frameshifts, 11 splice site mutations, and 13 missense mutations. Of the 59 different mutations identified, 54 were previously undescribed; 8 were observed more than once. Mutations were de novo in 40 of the 57 probands. Most of the observed mutations other than the missense mutations were expected to give rise to truncated and unanchored proteins. All mutations mapped to the extracellular domain of the protein, and there appeared to be regional hotspots, although no clustering was observed. Thus, sequencing of 7 of the 26 exons of the JAG1 gene would detect 51% of the mutations. Transmission analysis showed that 70% of the cases were sporadic.

Heritage et al. (2000) did a mutation screen in 22 individuals with ALGS from 19 Australian families. They identified 12 distinct JAG1 mutations in 15 (68.2%) of the patients; 7 of the mutations were novel.

Spinner et al. (2001) summarized data on 233 Alagille syndrome patients reported with mutations in JAG1. The data had been published by 7 different laboratories in Europe, the United States, Australia, and Japan. Mutations were demonstrated in 60 to 75% of patients with a clinically confirmed diagnosis of Alagille syndrome. Total gene deletions were reported in 3 to 7% of patients, and the remainder had intragenic mutations. In 168 of the 233 patients, the mutations led to frameshifts that caused a premature termination codon. These mutations would lead to a prematurely terminated protein, or alternatively, nonsense mediated decay might lead to lack of a product from that allele. Twenty-three unique missense mutations were found (13% of mutations). These were clustered in conserved regions at the 5-prime end of the gene, or in the EGF repeats.

Morrissette et al. (2001) studied 4 missense mutations (R184H; L37S, 601920.0011; P163L; and P871R) reported to cause Alagille syndrome. In 2 assays of JAG1 function, R184H and L37S were associated with loss of Notch signaling activity relative to wildtype JAG1. Neither R184H nor L37S was present on the cell surface, both were abnormally glycosylated, and there appeared to be abnormal accumulation of these proteins, possibly in the endoplasmic reticulum. Both P163L and P871R were associated with normal levels of Notch signaling activity and were present on the cell surface, suggesting to the authors that these changes may be polymorphisms rather than disease-causing mutations.

To explore the relationship between genotype and phenotype, Yuan et al. (2001) analyzed the JAG1 gene in 25 Japanese Alagille syndrome families at the genomic DNA level and identified 15 point mutations and 1 large deletion. Analysis of the genotype and phenotype strongly indicated that the Delta/Serrate/Lag2 (DSL) domain in the JAG1 protein plays an essential role in determining the severity of the liver disorder. In 4 sporadic cases, absence of an entire DSL domain in mutant JAG1 resulted in progressive liver failure, and all 4 patients required liver transplant at a very early age. In contrast, patients with a relatively mild liver disorder had an intact DSL domain in mutant JAG1. All 4 patients with severe liver disease had de novo mutations; 1 was a frameshift mutation in exon 2, 2 were nonsense mutations in exon 2, and a fourth had deletion of the entire JAG1 gene.

Giannakudis et al. (2001) detected parental mosaicism for a JAG1 mutation in 4 of 51 families where mutations had been identified in the ALGS patients and where parental DNA was available. The 4 mutations consisted of 3 single nucleotide substitutions and a 4-nucleotide insertion. In each of the 4 families, the parent with mosaicism exhibited only the characteristic face with or without an embryotoxon posterior but no other features of ALGS. Mosaicism was assessed if a significant signal reduction in SSCP, restriction, and/or sequence analysis was observed in comparison to a control reaction and by using up to 3 different primer pairs for a specific amplification. One case was observed where mosaicism was present in the patient himself, reflecting a somatic mosaicism due to a deletion of an undefined portion of the JAG1 gene (as determined using microsatellite D20S1154 from intron 19). The deletion was confirmed by FISH on metaphases of the patient, using a cosmid that harbors the entire JAG1 genomic sequence. Giannakudis et al. (2001) suggested that the high prevalence of parental mosaicism be taken into account in diagnosis, genetic counseling, and prognosis in ALGS. They also suggested that the high failure rate in mutation detection in ALGS patients may in part be due to mosaicism.

Gridley (2003) provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome, spondylocostal dysostosis (see 277300), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310).

Boyer et al. (2005) studied RNA products obtained from liver tissue of 5 patients with ALGS and from lymphoblastoid cell lines of 24 patients with ALGS. Mutant JAG1 transcripts were obtained in different relative amounts from RNAs with missense mutations or in-frame deletions, and from 19 of 21 RNAs with premature termination mutations. Results from lymphoblastoid cell lines correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of an affected 23-week-old fetus with a premature termination mutation. The findings suggested that most mutant transcripts with premature termination mutations escape nonsense-mediated mRNA decay and could lead to the synthesis of soluble forms of JAG1. Although haploinsufficiency is the main molecular mechanism responsible for ALGS, Boyer et al. (2005) concluded that the stability of most mutant JAG1 RNAs could also lead to the production of abnormal JAG1 proteins acting in a dominant-negative manner.

Boyer-Di Ponio et al. (2007) found that ALGS fetal fibroblasts and mouse fibroblasts expressing JAG1 with missense or nonsense mutations formed a network of cord-like structures in culture, in contrast to the even cell distribution of wildtype human or mouse fibroblasts. Pharmacologic inhibition of Notch signaling in wildtype cells resulted in the same phenotype. Coexpression of the mutant JAG1 proteins inhibited activation of a Notch reporter construct by wildtype JAG1. Boyer-Di Ponio et al. (2007) concluded that some ALGS-associated mutant JAG1 proteins can function as dominant-negative inhibitors of Notch signaling.

Birtel et al. (2018) reported a 24-year-old woman with bull's-eye retinopathy, double-outlet right ventricle, and severe scoliosis who was heterozygous for a frameshift mutation in the JAG1 gene (601920.0017).

Tetralogy of Fallot

Tetralogy of Fallot (TOF; 187500) is the most common form of complex congenital heart disease, occurring in 1 in 3,000 live births. Eldadah et al. (2001) identified a missense mutation (G274D; 601920.0010) in the JAG1 gene in a large kindred segregating autosomal dominant TOF with reduced penetrance. Nine of 11 mutation carriers manifested cardiac disease, including classic TOF, ventricular septal defect with aortic dextroposition, and isolated peripheral pulmonic stenosis. All forms of TOF were represented, including variants with pulmonic stenosis, pulmonic atresia, and absent pulmonary valve. No individual within this family met diagnostic criteria for any previously described clinical syndrome, including Alagille syndrome, caused by haploinsufficiency for the JAG1 gene. All mutation carriers had characteristic but variable facial features, including long, narrow, and upslanting palpebral fissures, prominent nasal bridge, square dental arch, and broad, prominent chin, which were distinct from those of unaffected family members and typical ALGS patients. The glycine at position 274 is highly conserved in other EGF-like domains of JAG1 and in those of other proteins. The authors proposed either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggested that JAG1 mutations may contribute significantly to common variants of right heart obstructive disease.

Axonal Charcot-Marie-Tooth Disease Type 2HH

In 9 affected individuals from 2 unrelated families with axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH; 619574), Sullivan et al. (2020) identified heterozygous missense mutations in the JAG1 gene (S577R, 601920.0015 and S650P, 601920.0016). Both mutations occurred at highly conserved residues in the extracellular domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither were present in the gnomAD database. In vitro expression studies showed that the mutations impaired protein glycosylation and reduced JAG1 surface expression compared to controls. Mutant JAG1 was partially retained in the endoplasmic reticulum (ER). Homozygous expression of the S577R mutation in mice was embryonic lethal. Heterozygous S577R mice showed impaired performance in a test of limb strength compared to wildtype, but were able to perform in the accelerating rotarod test. Electrophysiologic studies showed reduced compound muscle action potentials (CMAPs). Examination of the recurrent laryngeal nerve did not show significant axonal abnormalities, but there was some focally folded myelin. Sullivan et al. (2020) noted that none of the patients had features of Alagille syndrome (118450). The findings implicated JAG1 in the maintenance of peripheral nerve integrity and suggested that the neuropathy may result from altered Notch signaling.

Deafness, Congenital Heart Defects, and Posterior Embryotoxon

In affected members of a kindred with hearing loss, congenital heart defects, and posterior embryotoxon (DCHE; 617992) segregating as autosomal dominant traits, Le Caignec et al. (2002) identified heterozygosity for a missense mutation in the JAG1 gene (601920.0012).

Associations Pending Confirmation

For discussion of a possible association between variation in the JAG1 gene and bone mineral density, see BMND7 (611738).

For discussion of a possible association between variation in the JAG1 gene and exudative vitreoretinopathy, see EVR1 (133780).

▼ Animal Model
Kiernan et al. (2001) provided experimental evidence that Notch signaling may be involved in specifying sensory regions by showing that a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae. Heterozygotes also demonstrate a significant reduction in the number of outer hair cells in the organ of Corti. Because lateral inhibition mediated by Notch predicts that disruptions in this pathway would lead to an increase in hair cells, Kiernan et al. (2001) concluded that these data indicate an early role for Notch within the inner ear.

Tsai et al. (2001) identified a novel mouse mutant, 'slalom,' which demonstrated headweaving/shaking behavior and poor negative geotaxis indicative of a vestibular defect. Histopathologic analyses revealed abnormalities in the patterning of hair cells in the organ of Corti and missing ampullae, structures that house the sensory epithelia of the semicircular canals. The slalom mutant animals carried a C-to-T transition in the Jagged1 gene, resulting in a pro269-to-ser substitution in the second EGF-like repeat region. The authors hypothesized that alteration of this conserved amino acid may affect the interaction between Jagged1 and Notch receptors.

High et al. (2008) found that endothelial-specific deletion of Jag1 in mice resulted in embryonic lethality and cardiovascular defects, recapitulating the Jag1-null phenotype. Mutant embryos showed striking deficits in vascular smooth muscle, whereas endothelial Notch activation and arterial-venous differentiation appeared normal. Endothelial Jag1-mutant embryos were phenotypically distinct from embryos in which Notch signaling in endothelium was inhibited by a dominant-negative Maml (see MAML1, 605424) mutation. High et al. (2008) concluded that the primary role of endothelial JAG1 is to potentiate the development of neighboring vascular smooth muscle.

Duchenne muscular dystrophy (DMD; 310200) is caused by mutations in the dystrophin gene (DMD; 300377) that result in complete absence of dystrophin, leading to progressive myofiber degeneration and muscle wasting in affected individuals. The golden retriever muscular dystrophy (GRMD) model of DMD is caused by a splice-site mutation in the Dmd gene that causes skipping of exon 7, premature termination, and absence of dystrophin. Vieira et al. (2015) observed 2 GRMD 'escaper' dogs that remained fully ambulatory with normal lifespans. By genomewide mapping and gene expression analysis, they found that expression of Jag1 mRNA was 2-times higher in escaper GRMD muscle compared with wildtype and severely affected GRMD muscle. Sequence analysis revealed a heterozygous G-T change in the promoter region of the Jag1 gene in both escaper dogs that introduced a myogenin (MYOG; 159980) consensus binding motif. This Jag1 variant was absent in wildtype and severely affected GRMD dogs. EMSA and reporter gene analysis showed Myog binding and elevated reporter expression from the escaper Jag1 promoter but not the wildtype promoter. Introduction of escaper Jag1 rescued the muscle lethality phenotype of the zebrafish sapje model of DMD. Muscle cells from GRMD escaper dogs showed the typical dystrophic features of degeneration and regeneration, but escaper myogenic cells in culture divided significantly faster than those from severely affected dogs. Moreover, Vieira et al. (2015) found elevated Jag1 expression in mouse tibialis anterior muscle following cardiotoxin-induced injury and following myoblast differentiation in vitro. They concluded that elevated Jag1-dependent Notch signaling enhances the proliferative capacity of activated muscle satellite cells in escaper GRMD dogs.

Zhang et al. (2020) generated an endothelium-specific Jag1-knockout mouse model and observed delayed angiogenesis. At postnatal day 7, horizontal growth of retinal blood vessels was slower in the mutant mice than wildtype controls. Close examination of retinal whole-mounts revealed a sparse blood vessel network in the mutant retinas, with vessel density reduced to approximately 50% of that of control retinas. In addition, removal of Jag1 from endothelial cells resulted in a reduction in the number of tips and filopodia at the angiogenic front. Immunostaining of retinal frozen sections revealed profound defects in vertical vascular growth into the deeper retinal layers in the mutant compared to control retinas. No secondary or tertiary vessels were observed, and the vascular plexus became hyperplastic in the mutant retinas. The authors concluded that JAG1 plays a role in angiogenesis.

▼ ALLELIC VARIANTS ( 17 Selected Examples):

.0001 ALAGILLE SYNDROME 1
JAG1, 2-BP DEL, 3098GT
In their kindred C with Alagille syndrome (118450), Oda et al. (1997) demonstrated that the proband, her mother, and her sister had a frameshift in the JAG1 gene due to a 2-bp (GT) deletion in exon 22.

.0002 ALAGILLE SYNDROME 1
JAG1, IVS23DS, G-C, +1
In their Alagille syndrome (118450) kindred E, Oda et al. (1997) found an SSCP variant band only in the affected offspring. This was shown to be due to a mutation changing the normal splice donor signal GT to CT (3375+1G-C) at the exon 23/intron 23 junction.

.0003 ALAGILLE SYNDROME 1
JAG1, 2-BP DEL, 1104AG
In a family with Alagille syndrome (118450), Li et al. (1997) demonstrated deletion of 2 bp at positions 1104 and 1105 of the JAG1 gene. The deletion was located within exon 4, adjacent to the splice donor site. The deletion led to a shift in reading frame and premature termination codon at residue 240 (deleting 979 residues of the protein). Two affected brothers in this family had liver disease, heart disease (valvular and peripheral pulmonic stenosis), posterior embryotoxon, and 'Alagille facies.' Their less severely affected mother had a heart murmur, posterior embryotoxon, and Alagille facies.

.0004 ALAGILLE SYNDROME 1
JAG1, 1-BP DEL, 2066C
Li et al. (1997) demonstrated that affected members in a family with Alagille syndrome (118450) had deletion of 1 bp, 2066C, in exon 13. The proband was severely affected with liver and heart disease (tetralogy of Fallot), facial features, butterfly vertebrae, and posterior embryotoxon. Her father was mildly affected, with a history of heart murmur and characteristic facies.

.0005 ALAGILLE SYNDROME 1
JAG1, ARG184CYS
Krantz et al. (1998) identified 2 missense mutations among a total of 35 intragenic mutations in patients with Alagille syndrome (118450). Both occurred in codon 184 in exon 4A: arg184 to cys and arg184 to his (601920.0006).

.0006 ALAGILLE SYNDROME 1
JAG1, ARG184HIS
See 601920.0005 and Krantz et al. (1998). In 2 assays of JAG1 function, Morrissette et al. (2001) found that the R184H mutation was associated with loss of Notch signaling activity relative to wildtype JAG1. The protein containing the R184H substitution was not present on the cell surface, was abnormally glycosylated, and appeared to be abnormally accumulated, possibly in the endoplasmic reticulum.

.0007 ALAGILLE SYNDROME 1
JAG1, 5-BP DEL
In 2 unrelated patients with Alagille syndrome (118450), Krantz et al. (1998) identified a 5-bp deletion in exon 16 of the JAG1 gene.

.0008 ALAGILLE SYNDROME 1
JAG1, 1-BP INS, 1618C
In 2 unrelated patients with Alagille syndrome (118450), Krantz et al. (1998) identified a 1-bp insertion at nucleotide 1618 in the JAG1 gene.

.0009 ALAGILLE SYNDROME 1
JAG1, 1-BP INS, 684G
In a 3.5-year-old female with a 4-generation history of pulmonic stenosis and facial features consistent with Alagille syndrome (118450), Krantz et al. (1999) identified a 1-bp insertion at nucleotide 684 of the JAG1 gene, resulting in a premature stop codon at amino acid 745. The mutation was also identified in the patient's mother, who had pulmonic stenosis.

.0010 TETRALOGY OF FALLOT
JAG1, GLY274ASP
In a 4-generation pedigree exhibiting right-sided structural heart disease, including variants of tetralogy of Fallot (187500), Eldadah et al. (2001) identified an 821G-A transition, resulting in a gly274-to-asp substitution (G274D) in JAG1. Affected family members also had characteristic facies, but did not meet clinical diagnostic criteria for other syndromes associated with JAG1 haploinsufficiency.

Lu et al. (2003) noted that the G274D mutation carriers described by Eldadah et al. (2001) had cardiac defects of the type seen in Alagille syndrome (118450), e.g., peripheral pulmonic stenosis and tetralogy of Fallot, in the absence of liver dysfunction. Lu et al. (2003) reported data indicating that the G274D mutation is 'leaky.' Two populations of proteins were produced from the mutant allele: one was abnormally glycosylated and was retained intracellularly rather than being transported to the cell surface, and the other was normally glycosylated and was transported to the cell surface, where it was able to signal to the Notch receptor. The mutant protein was found to be temperature sensitive, with more abnormally glycosylated (and nonfunctional) molecules produced at higher temperatures. Carriers of this mutation therefore had more than 50%, but less than 100%, of the normal concentration of JAG1 molecules on the cell surface. The authors concluded that the cardiac-specific phenotype associated with this mutation suggests that the developing heart is more sensitive than the developing liver to decreased dosage of JAG1.

.0011 ALAGILLE SYNDROME 1
JAG1, LEU37SER
Morrissette et al. (2001) transfected 3T3 cells with a construct containing the missense mutation leu37 to ser (L37S), which is reported to cause Alagille syndrome. In 2 assays of JAG1 function, L37S was associated with loss of Notch signaling activity relative to wildtype JAG1. L37S was not present on the cell surface, was abnormally glycosylated, and appeared to be abnormally accumulated, possibly in the endoplasmic reticulum.

.0012 DEAFNESS, CONGENITAL HEART DEFECTS, AND POSTERIOR EMBRYOTOXON (1 family)
JAG1, CYS234TYR
In 7 affected members of a large family with mild to severe combined deafness, congenital heart defects, and posterior embryotoxon (DCHE; 617992) segregating as an autosomal dominant disorder, Le Caignec et al. (2002) detected heterozygosity for a G-to-A transition at nucleotide 701 in exon 5 of the JAG1 gene, resulting in a cys234-to-tyr (C234Y) substitution in the first epidermal growth factor (EGF)-like repeat domain. The mutation was not found in 7 unaffected family members or in 120 chromosomes from unrelated and unaffected individuals.

Bauer et al. (2010) investigated the functional significance of the C234Y variant. The C234Y mutant protein was sensitive to endoglycosidase H, suggesting that it is improperly posttranslationally modified. Whereas wildtype JAG1 is localized to the cell surface, trypsin degradation analysis and immunofluorescence showed no cell surface expression of C234Y mutant protein, consistent with its being retained intracellularly. Luciferase reporter assays showed that the C234Y mutant was unable to activate Notch signaling. Bauer et al. (2010) noted that residue 234 is located in the first EGF repeat of the JAG1 protein, in a region shown to be crucial for receptor-ligand interactions.

.0013 ALAGILLE SYNDROME 1
JAG1, 2-BP DEL, 1485CT
In a child with Alagille syndrome (118450) associated with coarctation of the abdominal aorta and right subclavian stenosis, Raas-Rothschild et al. (2002) identified a 1485delCT mutation in the JAG1 gene, leading to a stop codon (codon 504) 25 bp downstream from the deletion. The patient was the eighth child born of healthy first-cousin parents. At the age of 2 months he presented with prolonged jaundice. He was lost from follow-up until the age of 14 years, when he was referred to a gastroenterology clinic because of severe pruritus and headaches. His height was less than the third percentile. Blood pressure was reduced in the legs, and MRI revealed coarctation of the abdominal aorta which started just below the diaphragm and ended at the level of the renal arteries. There was bilateral renal artery stenosis, peripheral stenosis in the pulmonary arteries, and stenosis at the origin of the right subclavian artery.

.0014 ALAGILLE SYNDROME 1
JAG1, 1329, T-G, +2
In monozygotic twins with Alagille syndrome (118450) and severe but discordant clinical phenotypes, Kamath et al. (2002) identified a de novo splice site mutation in exon 6 of the JAG1 gene, a T-to-G substitution at nucleotide 1329+2. One of the mechanisms suggested by Kamath et al. (2002) to account for the discordance was that a splice site mutation could result in a variable amount of functional protein in different tissues.

.0015 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2HH
JAG1, SER577ARG
In 4 members of a 3-generation family (family 1) with axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH; 619574), Sullivan et al. (2020) identified a heterozygous c.1731C-G transversion in exon 14 of the JAG1 gene, resulting in a ser577-to-arg (S577R) substitution at a highly conserved residue in the extracellular domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. In vitro expression studies showed that the mutation impaired protein glycosylation and reduced JAG1 surface expression compared to controls. Mutant JAG1 was partially retained in the ER. Homozygous expression of the S577R mutation in mice was embryonic lethal. Heterozygous S577R mice showed impaired performance in a test of limb strength compared to wildtype, but were able to perform in the accelerating rotarod test. Electrophysiologic studies showed reduced CMAPs. Examination of the recurrent laryngeal nerve did not show significant axonal abnormalities, but there was some focally folded myelin. Sullivan et al. (2020) noted that the patients did not have features of Alagille syndrome (118450).

.0016 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2HH
JAG1, SER650PRO
In 5 members of a 2-generation family (family 2) with axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH; 619574), Sullivan et al. (2020) identified a heterozygous c.1948T-C transition in exon 15 of the JAG1 gene, resulting in a ser650-to-pro (S650P) substitution at a highly conserved residue in the extracellular domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. In vitro expression studies showed that the mutation impaired protein glycosylation and reduced JAG1 surface expression compared to controls. Sullivan et al. (2020) noted that the patients did not have features of Alagille syndrome (118450).

.0017 ALAGILLE SYNDROME 1
JAG1, 4-BP DEL, NT3164

In a 24-year-old woman (patient 184) with bull's-eye retinopathy, double-outlet right ventricle, and severe scoliosis (ALGS1; 118450), Birtel et al. (2018) identified heterozygosity for a 4-bp deletion (c.3164_3167del) in exon 25 of the ALGS1 gene, causing a frameshift predicted to result in a premature termination codon (Val1055GlufsTer7). The proband's unaffected mother did not carry the mutation; other family members were not available for study.

Tags: 20p12.2