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Article

JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families

  • Authors:
    • Erge Zhang
    • Yuejuan Xu
    • Yongguo Yu
    • Sun Chen
    • Yu Yu
    • Kun Sun
  • View Affiliations / Copyright

    Affiliations: Department of Pediatric Cardiology, Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China, Department of Pediatric Endocrinology and Genetics, Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China
  • Pages: 2356-2364
    |
    Published online on: June 25, 2018
       https://doi.org/10.3892/mmr.2018.9217
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Abstract

Alagille syndrome (ALGS) is primarily caused by jagged1 (JAG1) mutations, 70% of which are protein‑truncating mutations. However, no mutation hotspots have been discovered, and the pathogenic mechanism is not fully understood. The aim of the present study was to analyze two protein‑truncating JAG1 mutations detected in three Chinese ALGS patients. Mutation c.1261delT (p.Cys421Valfs) was identified in one patient with hepatic damage, xanthomas, facial abnormalities and cardiovascular defects, which was inherited from his father. The other mutation, c.1382_1383delAC (p.Asp461Glyfs), carried by a pair of monozygotic twins with hepatic damage, facial abnormalities and cardiovascular defects, was de novo. Biological experiments were performed to study the characteristics and function of these mutations. The p.Cys421Valfs and p.Asp461Glyfs mutant proteins appeared to be truncated in western blotting using anti‑Flag bound to the N‑terminus of JAG1. The RBP‑Jκ‑responsive reporter gene assay was used to investigate the ability of mutant JAG1 proteins to activate the Notch signaling pathway. The mutant proteins had a lower luciferase activity than the wild‑type, indicating impaired transcriptional activation ability. Western blotting using soluble JAG1 from the culture medium revealed that the expression levels of the mutant proteins were lower than that of the wild‑type, suggesting that less mutant JAG1 protein underwent proteolytic cleavage than the wild‑type. In conclusion, these two loss‑of‑function JAG1 mutations may be associated with ALGS manifestations in these patients.
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1 

Loomes KM, Underkoffler LA, Morabito J, Gottlieb S, Piccoli DA, Spinner NB, Baldwin HS and Oakey RJ: The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. Hum Mol Genet. 8:2443–2449. 1999. View Article : Google Scholar : PubMed/NCBI

2 

Giannakudis J, Röpke A, Kujat A, Krajewska-Walasek M, Hughes H, Fryns JP, Bankier A, Amor D, Schlicker M and Hansmann I: Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Eur J Hum Genet. 9:209–216. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Tada M, Itoh S, Ishii-Watabe A, Suzuki T and Kawasaki N: Functional analysis of the Notch ligand Jagged1 missense mutant proteins underlying Alagille syndrome. FEBS J. 279:2096–2107. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJ, Woyciechowski S, Garbarini J, Loomes KM, Krantz ID, Urban Z, et al: Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. Hum Mutat. 31:594–601. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Krantz ID, Piccoli DA and Spinner NB: Clinical and molecular genetics of Alagille syndrome. Curr Opin Pediatr. 11:558–564. 1999. View Article : Google Scholar : PubMed/NCBI

6 

Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, et al: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 16:243–251. 1997. View Article : Google Scholar : PubMed/NCBI

7 

Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS and Chandrasekharappa SC: Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 16:235–242. 1997. View Article : Google Scholar : PubMed/NCBI

8 

McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA and Spinner NB: NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 79:169–173. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Penton AL, Leonard LD and Spinner NB: Notch signaling in human development and disease. Semin Cell Dev Biol. 23:450–457. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Leonard LD, Chao G, Baker A, Loomes K and Spinner NB: Clinical utility gene card for: Alagille Syndrome (ALGS). Eur J Hum Genet. 22:2014.(doi: 10.1038/ejhg.2013). View Article : Google Scholar : PubMed/NCBI

11 

Turnpenny PD and Ellard S: Alagille syndrome: Pathogenesis, diagnosis and management. Eur J Hum Genet. 20:251–257. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, et al: NOTCH2 mutations in Alagille syndrome. J Med Genet. 49:138–144. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez-Lara PA, Piccoli DA, Krantz ID and Spinner NB: Jagged1 (JAG1) mutations in Alagille syndrome: Increasing the mutation detection rate. Hum Mutat. 27:436–443. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Boyer J, Crosnier C, Driancourt C, Raynaud N, Gonzales M, Hadchouel M and Meunier-Rotival M: Expression of mutant JAGGED1 alleles in patients with Alagille syndrome. Hum Genet. 116:445–453. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, Driancourt C, Beau I, Hadchouel M and Meunier-Rotival M: Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: Inhibitory effect on Notch signaling. Hum Mol Genet. 16:2683–2692. 2007. View Article : Google Scholar : PubMed/NCBI

16 

Morrissette JD, Colliton RP and Spinner NB: Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. Hum Mol Genet. 10:405–413. 2001. View Article : Google Scholar : PubMed/NCBI

17 

Liu C, Yang C, Lu L, Wang W, Tan W, Leung CH and Ma DL: Luminescent iridium(iii) complexes as COX-2-specific imaging agents in cancer cells. Chem Commun (Camb). 53:2822–2825. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Lincoln R, Greene LE, Zhang W, Louisia S and Cosa G: Mitochondria alkylation and cellular trafficking mapped with a lipophilic BODIPY-acrolein fluorogenic probe. J Am Chem Soc. 139:16273–16281. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Lin S, Gao W, Tian Z, Yang C, Lu L, Mergny JL, Leung CH and Ma DL: Luminescence switch-on detection of protein tyrosine kinase-7 using a G-quadruplex-selective probe. Chem Sci. 6:4284–4290. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Lu F, Morrissette JJ and Spinner NB: Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage. Am J Hum Genet. 72:1065–1070. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Zhang E, Hong N, Chen S, Fu Q, Li F, Yu Y and Sun K: Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects. Gene. 641:341–348. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Pu T, Liu Y, Xu R, Li F, Chen S and Sun K: Identification of ZFPM2 mutations in sporadic conotruncal heart defect patients. Mol Genet Genomics. 293:217–223. 2018. View Article : Google Scholar : PubMed/NCBI

23 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Li L, Dong J, Wang X, Guo H, Wang H, Zhao J, Qiu Y, Abuduxikuer K and Wang J: JAG1 mutation spectrum and origin in chinese children with clinical features of alagille syndrome. PLoS One. 10:e01303552015. View Article : Google Scholar : PubMed/NCBI

25 

Grochowski CM, Loomes KM and Spinner NB: Jagged1 (JAG1): Structure, expression, and disease associations. Gene. 576:381–384. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Chillakuri CR, Sheppard D, Lea SM and Handford PA: Notch receptor-ligand binding and activation: Insights from molecular studies. Semin Cell Dev Biol. 23:421–428. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, et al: A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat Struct Mol Biol. 15:849–857. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Lykke-Andersen S and Jensen TH: Nonsense-mediated mRNA decay: An intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol. 16:665–677. 2015. View Article : Google Scholar : PubMed/NCBI

29 

He F and Jacobson A: Nonsense-mediated mRNA decay: Degradation of defective transcripts is only part of the story. Annu Rev Genet. 49:339–366. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Mocquet V, Durand S and Jalinot P: How retroviruses escape the nonsense-mediated mRNA decay. AIDS Res Hum Retroviruses. 31:948–958. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Neu-Yilik G, Amthor B, Gehring NH, Bahri S, Paidassi H, Hentze MW and Kulozik AE: Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 17:843–854. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Ferraiuolo MA, Lee CS, Ler LW, Hsu JL, Costa-Mattioli M, Luo MJ, Reed R and Sonenberg N: A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in nonsense-mediated decay. Proc Natl Acad Sci USA. 101:4118–4123. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Neu-Yilik G, Gehring NH, Thermann R, Frede U, Hentze MW and Kulozik AE: Splicing and 3′end formation in the definition of nonsense-mediated decay-competent human beta-globin mRNPs. EMBO J. 20:532–540. 2001. View Article : Google Scholar : PubMed/NCBI

34 

Yuan ZR, Kobayashi N and Kohsaka T: Human Jagged 1 mutants cause liver defect in Alagille syndrome by overexpression of hepatocyte growth factor. J Mol Biol. 356:559–568. 2006. View Article : Google Scholar : PubMed/NCBI

35 

Sparks EE, Huppert KA, Brown MA, Washington MK and Huppert SS: Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology. 51:1391–1400. 2010. View Article : Google Scholar : PubMed/NCBI

36 

High FA and Epstein JA: The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet. 9:49–61. 2008. View Article : Google Scholar : PubMed/NCBI

37 

Humphreys R, Zheng W, Prince LS, Qu X, Brown C, Loomes K, Huppert SS, Baldwin S and Goudy S: Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet. 21:1374–1383. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Kamath BM, Bason L, Piccoli DA, Krantz ID and Spinner NB: Consequences of JAG1 mutations. J Med Genet. 40:891–895. 2003. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhang E, Xu Y, Yu Y, Chen S, Yu Y and Sun K: JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families. Mol Med Rep 18: 2356-2364, 2018.
APA
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., & Sun, K. (2018). JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families. Molecular Medicine Reports, 18, 2356-2364. https://doi.org/10.3892/mmr.2018.9217
MLA
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., Sun, K."JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families". Molecular Medicine Reports 18.2 (2018): 2356-2364.
Chicago
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., Sun, K."JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families". Molecular Medicine Reports 18, no. 2 (2018): 2356-2364. https://doi.org/10.3892/mmr.2018.9217
Copy and paste a formatted citation
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Spandidos Publications style
Zhang E, Xu Y, Yu Y, Chen S, Yu Y and Sun K: JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families. Mol Med Rep 18: 2356-2364, 2018.
APA
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., & Sun, K. (2018). JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families. Molecular Medicine Reports, 18, 2356-2364. https://doi.org/10.3892/mmr.2018.9217
MLA
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., Sun, K."JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families". Molecular Medicine Reports 18.2 (2018): 2356-2364.
Chicago
Zhang, E., Xu, Y., Yu, Y., Chen, S., Yu, Y., Sun, K."JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families". Molecular Medicine Reports 18, no. 2 (2018): 2356-2364. https://doi.org/10.3892/mmr.2018.9217
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