5bo1

Structural highlights

Disease

[JAG1_HUMAN] Defects in JAG1 are the cause of Alagille syndrome type 1 (ALGS1) [MIM:118450]. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]} Defects in JAG1 are a cause of tetralogy of Fallot (TOF) [MIM:187500]. TOF is a congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. This condition results in a blue baby at birth due to inadequate oxygenation. Surgical correction is emergent.^{[14] [15]}

Function

[JAG1_HUMAN] Ligand for multiple Notch receptors and involved in the mediation of Notch signaling. May be involved in cell-fate decisions during hematopoiesis. Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).^{[16] [17]}

References

1. ↑ Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997 Jul;16(3):243-51. PMID:9207788 doi:10.1038/ng0797-243
2. ↑ Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997 Jul;16(3):235-42. PMID:9207787 doi:10.1038/ng0797-235
3. ↑ Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. 1998 Jun;62(6):1361-9. PMID:9585603 doi:S0002-9297(07)62777-3
4. ↑ Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999 May;116(5):1141-8. PMID:10220506
5. ↑ Pilia G, Uda M, Macis D, Frau F, Crisponi L, Balli F, Barbera C, Colombo C, Frediani T, Gatti R, Iorio R, Marazzi MG, Marcellini M, Musumeci S, Nebbia G, Vajro P, Ruffa G, Zancan L, Cao A, DeVirgilis S. Jagged-1 mutation analysis in Italian Alagille syndrome patients. Hum Mutat. 1999;14(5):394-400. PMID:10533065 doi:<394::AID-HUMU5>3.0.CO;2-1 10.1002/(SICI)1098-1004(199911)14:5<394::AID-HUMU5>3.0.CO;2-1
6. ↑ Heritage ML, MacMillan JC, Colliton RP, Genin A, Spinner NB, Anderson GJ. Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population. Hum Mutat. 2000 Nov;16(5):408-16. PMID:11058898 doi:<408::AID-HUMU5>3.0.CO;2-9 10.1002/1098-1004(200011)16:5<408::AID-HUMU5>3.0.CO;2-9
7. ↑ Morrissette JD, Colliton RP, Spinner NB. Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 2001 Feb 15;10(4):405-13. PMID:11157803
8. ↑ Crosnier C, Driancourt C, Raynaud N, Hadchouel M, Meunier-Rotival M. Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Hum Mutat. 2001;17(1):72-3. PMID:11139247 doi:<72::AID-HUMU11>3.0.CO;2-U 10.1002/1098-1004(2001)17:1<72::AID-HUMU11>3.0.CO;2-U
9. ↑ Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Hum Mutat. 2001 Feb;17(2):151-2. PMID:11180599 doi:<151::AID-HUMU8>3.0.CO;2-T 10.1002/1098-1004(200102)17:2<151::AID-HUMU8>3.0.CO;2-T
10. ↑ Heritage ML, MacMillan JC, Anderson GJ. DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients. Hum Mutat. 2002 Dec;20(6):481. PMID:12442286 doi:10.1002/humu.9095
11. ↑ Ropke A, Kujat A, Graber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat. 2003 Jan;21(1):100. PMID:12497640 doi:10.1002/humu.9102
12. ↑ Jurkiewicz D, Popowska E, Glaser C, Hansmann I, Krajewska-Walasek M. Twelve novel JAG1 gene mutations in Polish Alagille syndrome patients. Hum Mutat. 2005 Mar;25(3):321. PMID:15712272 doi:10.1002/humu.9313
13. ↑ Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez-Lara PA, Piccoli DA, Krantz ID, Spinner NB. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat. 2006 May;27(5):436-43. PMID:16575836 doi:10.1002/humu.20310
14. ↑ Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997 Jul;16(3):235-42. PMID:9207787 doi:10.1038/ng0797-235
15. ↑ Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC. Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet. 2001 Jan 15;10(2):163-9. PMID:11152664
16. ↑ Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998 Jan;8(1):43-55. PMID:9462510
17. ↑ Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, Redfield C, Baron M, Lea SM, Handford PA. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat Struct Mol Biol. 2008 Aug;15(8):849-57. Epub 2008 Jul 27. PMID:18660822 doi:10.1038/nsmb.1457