Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome

Abstract

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by five major symptoms: cholestasis, vertebral deformity, heart malformations, ocular defects and peculiar facial appearance. The previously described Jagged1 (JAG1) gene on chromosome 20p12 has been identified as being responsible for AGS. JAG1 encodes a transmembrane protein acting as ligand for the evolutionarily conserved Notch signaling pathway. Here we report 36 novel mutations in the JAG1 gene. We identified 12 novel deletions, 4 insertions, 8 missense, 7 nonsense and 5 splice site mutations. All mutations map to the sequence encoding the extracellular part of the Jagged1 protein. The mutations spread over the entire gene with slightly increased rates in exons 2 to 6 and exon 23 and 24. Eight novel missense mutations map to the Delta-Serrate-Lag2 (DSL) domain and adjacent sequences which are important for ligand-receptor interaction. Inheritance was determined in 27 families. Sixteen mutations (55%) were de novo and eleven mutations (45%) were transmitted. Altogether 226 different JAG1 mutations have been described in association with AGS, including our novel 36 mutations. AGS variants are spread over the entire gene with only a few mutations in exon 26. A relatively high number of mutations are clustered in exons 2 to 6. This sequence region shows high interspecies conservation and encodes the Notch receptor-binding region (DSL domain).

Notch signaling: simplicity in design, versatility in function

“…Spondylocostal dysostosis (axial skeleton segmentation disorder) (Bonafe et al, 2003;Bulman et al, 2000;Turnpenny et al, 2003;Whittock et al, 2004) JAG1 Alagille syndrome; patients with JAG1 mutations display variable phenotypes in bile duct paucity, cardiac defects (including tetralogy of Fallot), posterior embryotoxon, spine defects (including butterfly vertebrae) and deafness (Bauer et al, 2010;Colliton et al, 2001;Crosnier et al, 1999;Crosnier et al, 2001;Eldadah et al, 2001;Heritage et al, 2002;Heritage et al, 2000; Krantz et al., 1998; Krantz et al, 1999; Li et al, 1997;Oda et al, 2000;Oda et al, 1997;Raas-Rothschild et al, 2002;Ropke et al, 2003;Stankiewicz et al, 2001;Warthen et al, 2006 DEVELOPMENT…”

“…Alagille syndrome; patients with JAG1 mutations display variable phenotypes in bile duct paucity, cardiac defects (including tetralogy of Fallot), posterior embryotoxon, spine defects (including butterfly vertebrae) and deafness (Bauer et al, 2010;Colliton et al, 2001;Crosnier et al, 1999;Crosnier et al, 2001;Eldadah et al, 2001;Heritage et al, 2002;Heritage et al, 2000;Krantz et al, 1998;Krantz et al, 1999;Li et al, 1997;Oda et al, 2000;Oda et al, 1997;Raas-Rothschild et al, 2002;Ropke et al, 2003;Stankiewicz et al, 2001;Warthen et al, 2006) LFNG Spondylocostal dysostosis (axial skeleton segmentation and growth disorder) (Sparrow et al, 2006) MAML2 Mucoepidermoid carcinoma, secondary acute myeloid leukemia (Conkright et al, 2003;Enlund et al, 2004;Tonon et al, 2003) NOTCH1 (Joutel et al, 1997a;Joutel et al, 2004;Joutel et al, 1997b;Oberstein et al, 1999) Skol et al, 2003;Tochigi et al, 2004;Wei and Hemmings, 2000) In addition to the canonical ligands mentioned above, a multitude of non-canonical ligands (reviewed by D'Souza et al, 2010) can activate or inhibit Notch signaling. An interesting example of a non-canonical ligand is Delta-like homolog 1/2 (Dlk1/2), which is structurally similar to the Dll ligands but lacks a DSL domain.…”

Alagille syndrome: pathogenesis, diagnosis and management

“…There are no particular hotspots, and any part of the entire coding region may be involved. 42,43 Gene deletions are found in up to 7% of cases, and there appears to be a critical region of 5.4 Mb, whereby the phenotype does not differ significantly from mutation cases. However, larger deletions are likely to be associated with additional problems such as learning difficulties.…”

Endocytosis in Notch Signaling Activation

“…Drosophila has two such ligand genes, Delta and Serrate, while there are five mammalian ligands, three belonging to the Delta-like family (Dll-1, -3 and -4) and two to the Jagged (Serrate homologous) family (Jagged-1 and -2). Starting from the N-terminus, the domain structure of the Notch ligands can be outlined as follows ( Fig.1): (i) a module at the N-terminus of Notch ligands (also known as the MNNL domain) of unknown structure but functionally relevant since Jag-1 mutations in this region are present in a subset of patients with the Alagille syndrome [99,100]; (ii) a DSL domain; (iii) a number of EGF-like repeats (ranging in number from 16 in the Jagged family to 5-9 in the Delta-like family); (iv) a cysteine-rich domain (CRD) present in Jagged but not in Dll ligands; (v) a transmembrane domain and (vi) an intracellular domain, highly divergent among Notch ligands, but with a conserved PDZ-binding domain in the mammalian Jagged-1, Delta-like-1 and -4. The function of this latter domain is unknown, although there is some evidence that its interaction with PDZ-containing adherens-junction proteins inhibits cell motility and favors epithelial cell assembly [101][102][103].…”