Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema

K. Gordon; D. Schulte; G. Brice; M.A. Simpson; M.G. Roukens; A. van Impel; F. Connell; K. Kalidas; S. Jeffery; P.S. Mortimer; S. Mansour; S. Schulte-Merker; P. Ostergaard

doi:10.1161/CIRCRESAHA.113.300350

Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema

K. Gordon, D. Schulte, G. Brice, M.A. Simpson, M.G. Roukens, A. van Impel, F. Connell, K. Kalidas, S. Jeffery, P.S. Mortimer, S. Mansour, S. Schulte-Merker, P. Ostergaard

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

139 Citations (Scopus)

Abstract

RATIONALE: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIVE: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. METHODS AND RESULTS: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. CONCLUSIONS: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.

Original language	English
Pages (from-to)	956-960
Journal	Circulation Research
Volume	112
Issue number	6
DOIs	https://doi.org/10.1161/CIRCRESAHA.113.300350
Publication status	Published - 2013

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Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., & Ostergaard, P. (2013). Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circulation Research, 112(6), 956-960. https://doi.org/10.1161/CIRCRESAHA.113.300350

@article{a2ac03cdaf1a483082d5704cea180fdb,

title = "Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema",

abstract = "RATIONALE: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIVE: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. METHODS AND RESULTS: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. CONCLUSIONS: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.",

author = "K. Gordon and D. Schulte and G. Brice and M.A. Simpson and M.G. Roukens and {van Impel}, A. and F. Connell and K. Kalidas and S. Jeffery and P.S. Mortimer and S. Mansour and S. Schulte-Merker and P. Ostergaard",

note = "Reporting year: 2013",

year = "2013",

doi = "10.1161/CIRCRESAHA.113.300350",

language = "English",

volume = "112",

pages = "956--960",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams & Wilkins",

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Gordon, K, Schulte, D, Brice, G, Simpson, MA, Roukens, MG, van Impel, A, Connell, F, Kalidas, K, Jeffery, S, Mortimer, PS, Mansour, S, Schulte-Merker, S & Ostergaard, P 2013, 'Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema', Circulation Research, vol. 112, no. 6, pp. 956-960. https://doi.org/10.1161/CIRCRESAHA.113.300350

Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. / Gordon, K.; Schulte, D.; Brice, G. et al.
In: Circulation Research, Vol. 112, No. 6, 2013, p. 956-960.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema

AU - Gordon, K.

AU - Schulte, D.

AU - Brice, G.

AU - Simpson, M.A.

AU - Roukens, M.G.

AU - van Impel, A.

AU - Connell, F.

AU - Kalidas, K.

AU - Jeffery, S.

AU - Mortimer, P.S.

AU - Mansour, S.

AU - Schulte-Merker, S.

AU - Ostergaard, P.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - RATIONALE: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIVE: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. METHODS AND RESULTS: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. CONCLUSIONS: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.

AB - RATIONALE: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIVE: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. METHODS AND RESULTS: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. CONCLUSIONS: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.

U2 - 10.1161/CIRCRESAHA.113.300350

DO - 10.1161/CIRCRESAHA.113.300350

M3 - Article

SN - 0009-7330

VL - 112

SP - 956

EP - 960

JO - Circulation Research

JF - Circulation Research

IS - 6

ER -

Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema

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