Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema

Molecular Syndromology

Volumn 4, Issue 6, 2013, Pages 257-266

  Mendola, A ^a   Schlogel M J ^a   Ghalamkarpour, A ^a   Irrthum, A ^a,c   Nguyen, H L ^a   Fastre E ^a   Bygum, A ^d   Van Der Vleuten, C ^e   Fagerberg, C ^d   Baselga, E ^f   Quere, I ^g   Mulliken, J B ^h   Boon, L M ^a,b   Brouillard, P ^a   Vikkula, M ^a,b  

^a DE DUVE INSTITUTE   (Belgium)

^b CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

^c Breast International Group   (Belgium)

^d ODENSE UNIVERSITY HOSPITAL   (Denmark)

^e RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^f UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^g MONTPELLIER UNIVERSITY HOSPITAL   (France)

^h BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

Functional pathway; Genetic; Mutation; Phenotype

Indexed keywords

CALCIUM BINDING PROTEIN; COLLAGEN AND CALCIUM BINDING EGF DOMAIN 1; GAP JUNCTION PROTEIN; GAP JUNCTION PROTEIN GAMMA 2; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 4; TRANSCRIPTION FACTOR FOXC2; TRANSCRIPTION FACTOR GATA 2; TRANSCRIPTION FACTOR SOX18; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR 3;

AMINO ACID SUBSTITUTION; ARTICLE; EXOME; FAMILIAL DISEASE; FAMILIAL LYMPHEDEMA; GENE FUNCTION; GENE IDENTIFICATION; GENE MUTATION; GENETIC ANALYSIS; HEREDITARY LYMPHEDEMA; HUMAN; INHERITANCE; LOSS OF FUNCTION MUTATION; LYMPHANGIOGENESIS; MAJOR CLINICAL STUDY; NONSENSE MUTATION; PENETRANCE; PRIORITY JOURNAL; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; STOP CODON;

EID: 84883738185     PISSN: 16618769     EISSN: 16618777     Source Type: Journal    
DOI: 10.1159/000354097     Document Type: Article

References (56)

1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 7: 248-249 (2010
2. Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41: 1272-1274 (2009
3. Alders M, Mendola A, Ades L, Al Gazali L, Bellini C, et al. Evaluation of clinical manifestations in patients with severe lymphedema with and without CCBE1 mutations. Mol Syndromol 4: 107-113 (2013
4. Au AC, Hernandez PA, Lieber E, Nadroo AM, Shen YM, et al. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am J Hum Genet 87: 436-444 (2010
5. Bell R, Brice G, Child AH, Murday VA, Mansour S, et al. Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene. Hum Genet 108: 546-551 (2001
6. Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, et al. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 3: 616 (2012
7. Boon LM, Vikkula M. Vascular Anomalies, in Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K (eds): Fitzpatricks Dermatology in General Medicine, ed 8 (Mc-Graw-Hill Professional Publishing, New York 2012
8. Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res 109: 486-491 (2011
9. Brice G, Child AH, Evans A, Bell R, Mansour S, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet 42: 98-102 (2005
10. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet 16: R140-R149 (2007
11. Butler MG, Dagenais SL, Rockson SG, Glover TW. A novel VEGFR3 mutation causes Milroy disease. Am J Med Genet A 143A: 1212-1217 (2007
12. Butler MG, Isogai S, Weinstein BM. Lymphatic development. Birth Defects Res C Embryo Today 87: 222-231 (2009
13. Cermenati S, Moleri S, Neyt C, Bresciani E, Carra S, et al. Sox18 genetically interacts with VegfC to regulate lymphangiogenesis in zebrafish. Arterioscler Thromb Vasc Biol 33: 1238-1247 (2013
14. Connell FC, Ostergaard P, Carver C, Brice G, Williams N, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet 124: 625-631 (2009
15. Connell F, Kalidas K, Ostergaard P, Brice G, Homfray T, et al. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet 127: 231-241 (2010
16. Dagenais SL, Hartsough RL, Erickson RP, Witte MH, Butler MG, Glover TW. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedemadistichiasis syndrome. Gene Expr Patterns 4: 611-619 (2004
17. Downes M, Francois M, Ferguson C, Parton RG, Koopman P. Vascular defects in a mouse model of hypotrichosis-lymphedema-Telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation. Hum Mol Genet 18: 2839-2850 (2009
18. Evans AL, Bell R, Brice G, Comeglio P, Lipede C, et al. Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet 40: 697-703 (2003
19. Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, et al. Mutations in FOXC2 (MFH-1) , a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67: 1382-1388 (2000
20. Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet 86: 943-948 (2010
21. Finegold D, Baty C, Knickelbein K, Perschke S, Noon S, et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res 18: 2382-2890 (2012
22. Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature 456: 643-647 (2008
23. Futatani T, Nii E, Obata M, Ichida F, Okabe Y, et al. Molecular characterization of two novel VEGFR3 mutations in Japanese families with Milroys disease. Pediatr Int 50: 116-118 (2008
24. Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken JB, et al. Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Clin Genet 70: 330-335 (2006
25. Ghalamkarpour A, Debauche C, Haan E, Van Regemorter N, Sznajer Y, et al. Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2 . J Pediatr 155: 90-93 (2009a
26. Ghalamkarpour A, Holnthoner W, Saharinen P, Boon LM, Mulliken JB, et al. Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. J Med Genet 46: 399-404 (2009b
27. Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroylike primary lymphedema. Circ Res 112: 956-960 (2013
28. Hagerling R, Pollmann C, Andreas M, Schmidt C, Nurmi H, et al. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 32: 629-644 (2013
29. Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43: 1012-1017 (2011
30. Hennekam RC, Geerdink RA, Hamel BC, Hennekam FA, Kraus P, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34: 593-600 (1989
31. Hogan BM, Bos FL, Bussmann J, Witte M, Chi NC, et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 41: 396-398 (2009
32. Holme H, Hossain U, Kirwan M, Walne A, Vulliamy T, Dokal I. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol 158: 242-248 (2012
33. Hyde RK, Liu PP. GATA2 mutations lead to MDS and AML. Nat Genet 43: 926-927 (2011
34. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 67: 295-301 (2000
35. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-Telangiectasia. Am J Hum Genet 72: 1470-1478 (2003
36. Ishida H, Imai K, Honma K, Tamura SI, Imamura T, et al. GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B-And NK-cell (DCML) deficiency, and myelodysplasia. Eur J Pediatr 171: 1273-1276 (2012
37. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19: 5598-5605 (2000
38. Karkkainen MJ, Jussila L, Ferrell RE, Finegold DN, Alitalo K. Molecular regulation of lymphangiogenesis and targets for tissue oedema. Trends Mol Med 7: 18-22 (2001
39. Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119: 1283-1291 (2012
40. Norrmen C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 185: 439-457 (2009
41. Ostergaard P, Simpson MA, Brice G, Mansour S, Connell FC, et al. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet 48: 251-255 (2011a
42. Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 43: 929-931 (2011b
43. Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet 90: 356-362 (2012
44. Pennisi D, Bowles J, Nagy A, Muscat G, Koopman P. Mice null for Sox18 are viable and display a mild coat defect. Mol Cell Biol 20: 9331-9336 (2000a
45. Pennisi D, Gardner J, Chambers D, Hosking B, Peters J, et al. Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice. Nat Genet 24: 434-437 (2000b
46. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10: 974-981 (2004
47. Ramensky V, Bork P, Sunyaev S. Human nonsynonymous SNPs: server and survey. Nucleic Acids Res 30: 3894-3900 (2002
48. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7: 575-576 (2010
49. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29: 308-311 (2001
50. Shimoda H, Bernas MJ, Witte MH. Dysmorphogenesis of lymph nodes in Foxc2 haploinsufficient mice. Histochem Cell Biol 135: 603-613 (2011
51. Sunyaev SR, Eisenhaber F, Rodchenkov IV, Eisenhaber B, Tumanyan VG, Kuznetsov EN. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein Eng 12: 387-394 (1999
52. Uhlenberg B, Schuelke M, Ruschendorf F, Ruf N, Kaindl AM, et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 75: 251-260 (2004
53. van Steensel MA, Damstra RJ, Heitink MV, Bladergroen RS, Veraart J, et al. Novel missense mutations in the FOXC2 gene alter transcriptional activity. Hum Mutat 30: E1002-E1009 (2009
54. Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y. Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation. J Cell Sci 113: 3117-3123 (2000
55. Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE. Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29: 6-13 (2008
56. Zou Z, Enis DR, Bui H, Khandros E, Kumar V, et al. The secreted lymphangiogenic factor CCBE1 is essential for fetal liver erythropoiesis. Blood 121: 3228-3236 (2013