Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Patricia E. Burrows, Manuel L. Gonzalez-Garay, John C. Rasmussen, Melissa B. Aldrich, Renie Guilliod, Erik A. Maus, Caroline E. Fife, Sunkuk Kwon, Philip E. Lapinski, Philip D. King, Eva M. Sevick-Muraca

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Abstract

Mutations in gene RASA1 have been historically associated with capillarymalformation-arteriovenousmalformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes-Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.

Original languageEnglish (US)
Pages (from-to)8621-8626
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number21
DOIs
StatePublished - May 21 2013

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Lymphatic Abnormalities
Sturge-Weber Syndrome
Exome
Mutation
Groin
Optical Imaging
Fathers
Genes
Coloring Agents
Chylous Ascites
Lymphocele
Modifier Genes
Lymphography
Lymphatic System
Skin
Indocyanine Green
Penetrance
Nuclear Family
DNA Sequence Analysis
Knockout Mice

Keywords

  • CM-AVM
  • Indocyanine green imaging
  • Lymphatics
  • Near-infrared fluorescence imaging

ASJC Scopus subject areas

  • General

Cite this

Burrows, P. E., Gonzalez-Garay, M. L., Rasmussen, J. C., Aldrich, M. B., Guilliod, R., Maus, E. A., ... Sevick-Muraca, E. M. (2013). Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proceedings of the National Academy of Sciences of the United States of America, 110(21), 8621-8626. https://doi.org/10.1073/pnas.1222722110

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. / Burrows, Patricia E.; Gonzalez-Garay, Manuel L.; Rasmussen, John C.; Aldrich, Melissa B.; Guilliod, Renie; Maus, Erik A.; Fife, Caroline E.; Kwon, Sunkuk; Lapinski, Philip E.; King, Philip D.; Sevick-Muraca, Eva M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 21, 21.05.2013, p. 8621-8626.

Research output: Contribution to journalArticle

Burrows, PE, Gonzalez-Garay, ML, Rasmussen, JC, Aldrich, MB, Guilliod, R, Maus, EA, Fife, CE, Kwon, S, Lapinski, PE, King, PD & Sevick-Muraca, EM 2013, 'Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 21, pp. 8621-8626. https://doi.org/10.1073/pnas.1222722110
Burrows, Patricia E. ; Gonzalez-Garay, Manuel L. ; Rasmussen, John C. ; Aldrich, Melissa B. ; Guilliod, Renie ; Maus, Erik A. ; Fife, Caroline E. ; Kwon, Sunkuk ; Lapinski, Philip E. ; King, Philip D. ; Sevick-Muraca, Eva M. / Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 21. pp. 8621-8626.
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