Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Rare Germline GLMN Variants Identified from Blue Rubber Bleb Nevus Syndrome Might Impact mTOR Signaling

Author(s): Jie Yin, Zhongping Qin, Kai Wu, Yufei Zhu, Landian Hu and Xiangyin Kong*

Volume 22, Issue 10, 2019

Page: [675 - 682] Pages: 8

DOI: 10.2174/1386207322666191203110042

Price: $65

Abstract

Background and Objective: Blue rubber bleb nevus syndrome (BRBN) or Bean syndrome is a rare Venous Malformation (VM)-associated disorder, which mostly affects the skin and gastrointestinal tract in early childhood. Somatic mutations in TEK have been identified from BRBN patients; however, the etiology of TEK mutation-negative patients of BRBN need further investigation.

Methods: Two unrelated sporadic BRBNs and one sporadic VM were firstly screened for any rare nonsilent mutation in TEK by Sanger sequencing and subsequently applied to whole-exome sequencing to identify underlying disease causative variants. Overexpression assay and immunoblotting were used to evaluate the functional effect of the candidate disease causative variants.

Results: In the VM case, we identified the known causative somatic mutation in the TEK gene c.2740C>T (p.Leu914Phe). In the BRBN patients, we identified two rare germline variants in GLMN gene c.761C>G (p.Pro254Arg) and c.1630G>T(p.Glu544*). The GLMN-P254R-expressing and GLMN-E544X-expressing HUVECs exhibited increased phosphorylation of mTOR-Ser-2448 in comparison with GLMN-WTexpressing HUVECs in vitro.

Conclusion: Our results demonstrated that rare germline variants in GLMN might contribute to the pathogenesis of BRBN. Moreover, abnormal mTOR signaling might be the pathogenesis mechanism underlying the dysfunction of GLMN protein.

Keywords: Blue rubber bleb nevus syndrome, venous malformation, GLMN, mTOR, bean syndrome, TEK.

[1]
Bean, W.B. Enteric bleeding in rare conditions with diagnostic lesions of the skin and mucous membrane. Trans. Am. Clin. Climatol. Assoc., 1957-1958, 69, 72-86.
[PMID: 13581089]
[2]
Moodley, M.; Ramdial, P. Blue rubber bleb nevus syndrome: case report and review of the literature. Pediatrics, 1993, 92(1), 160-162.
[PMID: 8516068]
[3]
Fishman, S.J.; Smithers, C.J.; Folkman, J.; Lund, D.P.; Burrows, P.E.; Mulliken, J.B.; Fox, V.L. Blue rubber bleb nevus syndrome: surgical eradication of gastrointestinal bleeding. Ann. Surg., 2005, 241(3), 523-528.
[http://dx.doi.org/10.1097/01.sla.0000154689.85629.93] [PMID: 15729077]
[4]
Dompmartin, A.; Vikkula, M.; Boon, L.M. Venous malformation: update on aetiopathogenesis, diagnosis and management. Phlebology / Venous Forum of the Royal Society of Medicine,, 2010, 25(5), 224-235.
[5]
Boon, L.M.; Mulliken, J.B.; Vikkula, M.; Watkins, H.; Seidman, J.; Olsen, B.R.; Warman, M.L. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum. Mol. Genet., 1994, 3(9), 1583-1587.
[http://dx.doi.org/10.1093/hmg/3.9.1583] [PMID: 7833915]
[6]
Vikkula, M.; Boon, L.M.; Carraway, K.L., III; Calvert, J.T.; Diamonti, A.J.; Goumnerov, B.; Pasyk, K.A.; Marchuk, D.A.; Warman, M.L.; Cantley, L.C.; Mulliken, J.B.; Olsen, B.R. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell, 1996, 87(7), 1181-1190.
[http://dx.doi.org/10.1016/S0092-8674(00)81814-0] [PMID: 8980225]
[7]
Calvert, J.T.; Riney, T.J.; Kontos, C.D.; Cha, E.H.; Prieto, V.G.; Shea, C.R.; Berg, J.N.; Nevin, N.C.; Simpson, S.A.; Pasyk, K.A.; Speer, M.C.; Peters, K.G.; Marchuk, D.A. Allelic and locus heterogeneity in inherited venous malformations. Hum. Mol. Genet., 1999, 8(7), 1279-1289.
[http://dx.doi.org/10.1093/hmg/8.7.1279] [PMID: 10369874]
[8]
Limaye, N.; Wouters, V.; Uebelhoer, M.; Tuominen, M.; Wirkkala, R.; Mulliken, J.B.; Eklund, L.; Boon, L.M.; Vikkula, M. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat. Genet., 2009, 41(1), 118-124.
[http://dx.doi.org/10.1038/ng.272] [PMID: 19079259]
[9]
Soblet, J.; Limaye, N.; Uebelhoer, M.; Boon, L.M.; Vikkula, M. Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol. Syndromol., 2013, 4(4), 179-183.
[PMID: 23801934]
[10]
Soblet, J.; Kangas, J.; Nätynki, M.; Mendola, A.; Helaers, R.; Uebelhoer, M.; Kaakinen, M.; Cordisco, M.; Dompmartin, A.; Enjolras, O.; Holden, S.; Irvine, A.D.; Kangesu, L.; Léauté-Labrèze, C.; Lanoel, A.; Lokmic, Z.; Maas, S.; McAleer, M.A.; Penington, A.; Rieu, P.; Syed, S.; van der Vleuten, C.; Watson, R.; Fishman, S.J.; Mulliken, J.B.; Eklund, L.; Limaye, N.; Boon, L.M.; Vikkula, M. Blue Rubber Bleb Nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. J. Invest. Dermatol., 2017, 137(1), 207-216.
[http://dx.doi.org/10.1016/j.jid.2016.07.034] [PMID: 27519652]
[11]
Nätynki, M.; Kangas, J.; Miinalainen, I.; Sormunen, R.; Pietilä, R.; Soblet, J.; Boon, L.M.; Vikkula, M.; Limaye, N.; Eklund, L. Common and specific effects of TIE2 mutations causing venous malformations. Hum. Mol. Genet., 2015, 24(22), 6374-6389.
[http://dx.doi.org/10.1093/hmg/ddv349] [PMID: 26319232]
[12]
Limaye, N.; Kangas, J.; Mendola, A.; Godfraind, C.; Schlögel, M.J.; Helaers, R.; Eklund, L.; Boon, L.M.; Vikkula, M. Somatic activating PIK3CA mutations cause venous malformation. Am. J. Hum. Genet., 2015, 97(6), 914-921.
[http://dx.doi.org/10.1016/j.ajhg.2015.11.011] [PMID: 26637981]
[13]
Brouillard, P.; Boon, L.M.; Mulliken, J.B.; Enjolras, O.; Ghassibé, M.; Warman, M.L.; Tan, O.T.; Olsen, B.R.; Vikkula, M. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (“glomangiomas”). Am. J. Hum. Genet., 2002, 70(4), 866-874.
[http://dx.doi.org/10.1086/339492] [PMID: 11845407]
[14]
Brouillard, P.; Boon, L.M.; Revencu, N.; Berg, J.; Dompmartin, A.; Dubois, J.; Garzon, M.; Holden, S.; Kangesu, L.; Labrèze, C.; Lynch, S.A.; McKeown, C.; Meskauskas, R.; Quere, I.; Syed, S.; Vabres, P.; Wassef, M.; Mulliken, J.B.; Vikkula, M. GVM Study Group.Genotypes and phenotypes of 162 families with a glomulin mutation. Mol. Syndromol., 2013, 4(4), 157-164.
[PMID: 23801931]
[15]
Choi, M.; Scholl, U.I.; Ji, W.; Liu, T.; Tikhonova, I.R.; Zumbo, P.; Nayir, A.; Bakkaloğlu, A.; Ozen, S.; Sanjad, S.; Nelson-Williams, C.; Farhi, A.; Mane, S.; Lifton, R.P. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. USA, 2009, 106(45), 19096-19101.
[http://dx.doi.org/10.1073/pnas.0910672106] [PMID: 19861545]
[16]
Bamshad, M.J.; Ng, S.B.; Bigham, A.W.; Tabor, H.K.; Emond, M.J.; Nickerson, D.A.; Shendure, J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet., 2011, 12(11), 745-755.
[http://dx.doi.org/10.1038/nrg3031] [PMID: 21946919]
[17]
Koressaar, T.; Remm, M. Enhancements and modifications of primer design program Primer3. Bioinformatics, 2007, 23(10), 1289-1291.
[http://dx.doi.org/10.1093/bioinformatics/btm091] [PMID: 17379693]
[18]
BroadInstitute Picardtools, 2018.
[19]
DePristo, M.A.; Banks, E.; Poplin, R.; Garimella, K.V.; Maguire, J.R.; Hartl, C.; Philippakis, A.A.; del Angel, G.; Rivas, M.A.; Hanna, M.; McKenna, A.; Fennell, T.J.; Kernytsky, A.M.; Sivachenko, A.Y.; Cibulskis, K.; Gabriel, S.B.; Altshuler, D.; Daly, M.J. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet., 2011, 43(5), 491-498.
[http://dx.doi.org/10.1038/ng.806] [PMID: 21478889]
[20]
Saunders, C.T.; Wong, W.S.; Swamy, S.; Becq, J.; Murray, L.J.; Cheetham, R.K. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics, 2012, 28(14), 1811-1817.
[http://dx.doi.org/10.1093/bioinformatics/bts271] [PMID: 22581179]
[21]
Favero, F.; Joshi, T.; Marquard, A.M.; Birkbak, N.J.; Krzystanek, M.; Li, Q.; Szallasi, Z.; Eklund, A.C. Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data. Ann. Oncol., 2015, 26(1), 64-70.
[22]
Wang, K.; Li, M.; Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 2010, 38(16)e164
[http://dx.doi.org/10.1093/nar/gkq603] [PMID: 20601685]
[23]
Ng, P.C.; Henikoff, S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res., 2003, 31(13), 3812-3814.
[http://dx.doi.org/10.1093/nar/gkg509] [PMID: 12824425]
[24]
Adzhubei, I.; Jordan, D.M.; Sunyaev, S.R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protocols, 2013, 76(1), 7.20.1-7.20.41.
[http://dx.doi.org/10.1002/0471142905.hg0720s76]
[25]
Edgar, R.C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res., 2004, 32(5), 1792-1797.
[http://dx.doi.org/10.1093/nar/gkh340] [PMID: 15034147]
[26]
Chen, J.; Bardes, E.E.; Aronow, B. J.; Jegga, A.G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res.,, 2009, 37(Web Server issue), W305-11.
[27]
PrimerX software by Lapid, C.; Gao, Y. 2003.
[28]
Davis, S.; Aldrich, T.H.; Jones, P.F.; Acheson, A.; Compton, D.L.; Jain, V.; Ryan, T.E.; Bruno, J.; Radziejewski, C.; Maisonpierre, P.C.; Yancopoulos, G.D. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell, 1996, 87(7), 1161-1169.
[http://dx.doi.org/10.1016/S0092-8674(00)81812-7] [PMID: 8980223]
[29]
Wouters, V.; Limaye, N.; Uebelhoer, M.; Irrthum, A.; Boon, L.M.; Mulliken, J.B.; Enjolras, O.; Baselga, E.; Berg, J.; Dompmartin, A.; Ivarsson, S.A.; Kangesu, L.; Lacassie, Y.; Murphy, J.; Teebi, A.S.; Penington, A.; Rieu, P.; Vikkula, M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur. J. Hum. Genet., 2010, 18(4), 414-420.
[http://dx.doi.org/10.1038/ejhg.2009.193] [PMID: 19888299]
[30]
Koboldt, D.C.; Zhang, Q.; Larson, D.E.; Shen, D.; McLellan, M.D.; Lin, L.; Miller, C.A.; Mardis, E.R.; Ding, L.; Wilson, R.K. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res., 2012, 22(3), 568-576.
[http://dx.doi.org/10.1101/gr.129684.111] [PMID: 22300766]
[31]
Dickinson, M.E.; Flenniken, A.M.; Ji, X.; Teboul, L.; Wong, M.D.; White, J.K.; Meehan, T.F.; Weninger, W.J.; Westerberg, H.; Adissu, H.; Baker, C.N.; Bower, L.; Brown, J.M.; Caddle, L.B.; Chiani, F.; Clary, D.; Cleak, J.; Daly, M.J.; Denegre, J.M.; Doe, B.; Dolan, M.E.; Edie, S.M.; Fuchs, H.; Gailus-Durner, V.; Galli, A.; Gambadoro, A.; Gallegos, J.; Guo, S.; Horner, N.R.; Hsu, C.W.; Johnson, S.J.; Kalaga, S.; Keith, L.C.; Lanoue, L.; Lawson, T.N.; Lek, M.; Mark, M.; Marschall, S.; Mason, J.; McElwee, M.L.; Newbigging, S.; Nutter, L.M.; Peterson, K.A.; Ramirez-Solis, R.; Rowland, D.J.; Ryder, E.; Samocha, K.E.; Seavitt, J.R.; Selloum, M.; Szoke-Kovacs, Z.; Tamura, M.; Trainor, A.G.; Tudose, I.; Wakana, S.; Warren, J.; Wendling, O.; West, D.B.; Wong, L.; Yoshiki, A.; MacArthur, D.G.; Tocchini-Valentini, G.P.; Gao, X.; Flicek, P.; Bradley, A.; Skarnes, W.C.; Justice, M.J.; Parkinson, H.E.; Moore, M.; Wells, S.; Braun, R.E.; Svenson, K.L.; de Angelis, M.H.; Herault, Y.; Mohun, T.; Mallon, A.M.; Henkelman, R.M.; Brown, S.D.; Adams, D.J.; Lloyd, K.C.; McKerlie, C.; Beaudet, A.L.; Bućan, M.; Murray, S.A. International Mouse Phenotyping Consortium.Jackson Laboratory; Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS); Charles River Laboratories; MRC Harwell; Toronto Centre for Phenogenomics; Wellcome Trust Sanger Institute; RIKEN BioResource Center. High-throughput discovery of novel developmental phenotypes. Nature, 2016, 537(7621), 508-514.
[http://dx.doi.org/10.1038/nature19356] [PMID: 27626380]
[32]
Grisendi, S.; Chambraud, B.; Gout, I.; Comoglio, P.M.; Crepaldi, T. Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor. J. Biol. Chem., 2001, 276(49), 46632-46638.
[http://dx.doi.org/10.1074/jbc.M104323200] [PMID: 11571281]
[33]
Brouillard, P.; Ghassibé, M.; Penington, A.; Boon, L.M.; Dompmartin, A.; Temple, I.K.; Cordisco, M.; Adams, D.; Piette, F.; Harper, J.I.; Syed, S.; Boralevi, F.; Taïeb, A.; Danda, S.; Baselga, E.; Enjolras, O.; Mulliken, J.B.; Vikkula, M. Four common glomulin mutations cause two thirds of glomuvenous malformations (“familial glomangiomas”): evidence for a founder effect. J. Med. Genet., 2005, 42(2)e13
[http://dx.doi.org/10.1136/jmg.2004.024174] [PMID: 15689436]
[34]
Boscolo, E.; Limaye, N.; Huang, L.; Kang, K.T.; Soblet, J.; Uebelhoer, M.; Mendola, A.; Natynki, M.; Seront, E.; Dupont, S.; Hammer, J.; Legrand, C.; Brugnara, C.; Eklund, L.; Vikkula, M.; Bischoff, J.; Boon, L.M. Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J. Clin. Invest., 2015, 125(9), 3491-3504.
[http://dx.doi.org/10.1172/JCI76004] [PMID: 26258417]
[35]
Chiang, G.G.; Abraham, R.T. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J. Biol. Chem., 2005, 280(27), 25485-25490.
[http://dx.doi.org/10.1074/jbc.M501707200] [PMID: 15899889]
[36]
Duda, D.M.; Olszewski, J.L.; Tron, A.E.; Hammel, M.; Lambert, L.J.; Waddell, M.B.; Mittag, T.; DeCaprio, J.A.; Schulman, B.A. Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Mol. Cell, 2012, 47(3), 371-382.
[http://dx.doi.org/10.1016/j.molcel.2012.05.044] [PMID: 22748924]
[37]
Lewis, B.P.; Green, R.E.; Brenner, S.E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl. Acad. Sci. USA, 2003, 100(1), 189-192.
[http://dx.doi.org/10.1073/pnas.0136770100] [PMID: 12502788]
[38]
Amyere, M.; Aerts, V.; Brouillard, P.; McIntyre, B.A.; Duhoux, F.P.; Wassef, M.; Enjolras, O.; Mulliken, J.B.; Devuyst, O.; Antoine-Poirel, H.; Boon, L.M.; Vikkula, M. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am. J. Hum. Genet., 2013, 92(2), 188-196.
[http://dx.doi.org/10.1016/j.ajhg.2012.12.017] [PMID: 23375657]
[39]
Birchmeier, C.; Gherardi, E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol., 1998, 8(10), 404-410.
[http://dx.doi.org/10.1016/S0962-8924(98)01359-2] [PMID: 9789329]
[40]
Arai, T.; Kasper, J.S.; Skaar, J.R.; Ali, S.H.; Takahashi, C.; DeCaprio, J.A. Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc. Natl. Acad. Sci. USA, 2003, 100(17), 9855-9860.
[http://dx.doi.org/10.1073/pnas.1733908100] [PMID: 12904573]
[41]
Tron, A.E.; Arai, T.; Duda, D.M.; Kuwabara, H.; Olszewski, J.L.; Fujiwara, Y.; Bahamon, B.N.; Signoretti, S.; Schulman, B.A.; DeCaprio, J.A. The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Mol. Cell, 2012, 46(1), 67-78.
[http://dx.doi.org/10.1016/j.molcel.2012.02.005] [PMID: 22405651]
[42]
Mao, J-H.; Kim, I-J.; Wu, D.; Climent, J.; Kang, H.C.; DelRosario, R.; Balmain, A. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science, 2008, 321(5895), 1499-1502.
[http://dx.doi.org/10.1126/science.1162981] [PMID: 18787170]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy